Research initiatives and grants

Published

2020-02-18

Updated

2021-02-01

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Project manager	Administrator of appropriations	Project title	Subject matter	Year	Details
Hans Ellegren	Kungl. Academy of Sciences	Torsten Söderberg Academy Professorship in Medicine 2025	Medicine	2024	Amount awarded: SEK 10 000 000 There is a great need for this type of grant, where outstanding researchers are given the opportunity to develop and deepen their research. This is an important part of further strengthening Swedish research in the light of international developments. The professorship will promote internationally leading research in the field of medicine by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed on the basis of documented scientific quality of the research performed. Particular emphasis will be placed on research carried out during the last five-year period. The quality of the research program, the degree of innovation and the importance for the development of medical research will also be assessed. Kungl. The Royal Swedish Academy of Sciences is therefore applying for a grant of SEK 10 million to fill a new five-year academic professorship in medicine in 2025.
Henrik Ehrsson	Karolinska Institute	Brain mechanisms behind the experience of body unity	Medicine	2024	Amount granted: SEK 250 000 Have you ever wondered why you feel your body as a single entity, even though it is made up of many different parts? Or why you can only feel one body as your own, and not several at once? This fascinating mystery is at the heart of our groundbreaking research project. We are using advanced brain imaging techniques and novel illusion experiments to map out how the brain creates our sense of a coherent body experience. We are investigating how sensory information from different body parts, including the head, is integrated into a coherent whole. The project will give us new insights into how coherent body perception is created in the brain. In addition, the results may pave the way for a better understanding of psychiatric conditions where self-perception is disturbed, such as in schizophrenia. By revealing the brain mechanisms behind our bodily self-perception, this project opens the door to a deeper understanding of what it means to be human.
Aishe Sarshad	University of Gothenburg	Gene regulation of RNA-binding proteins in aging: Insights from human models	Medicine	2024	Amount granted: SEK 600 000 RNA interference (RNAi) is a natural process that helps control which genes are active and keeps cells functioning properly. When this process doesn't work properly, it can lead to diseases. RNAi works through proteins called Argonaute (AGO) and small RNA molecules called miRNAs, which attach to messenger RNAs (mRNAs) and cause them to be degraded. Although we know a lot about how RNAi works in the main part of the cell (the cytoplasm), recent research shows that RNAi also occurs in the nucleus. My lab studies how RNAi works in the nucleus and how it affects health and disease. We have learned that the protein AGO is important in the nucleus during early development, but is normally kept outside the nucleus in healthy adult cells. However, during viral infections, cancer and even ageing, AGO can end up in the nucleus, which can worsen the disease/condition. Blocking AGO in the nucleus could therefore be a new way to treat these conditions. RNAi is increasingly recognized for its role in regulating aging, a complex process shaped by genetic, environmental and cellular factors. In this project, we will investigate the relationship between RNAi and aging, with a particular focus on nuclear RNAi processes. To achieve these goals, we will use patient cells from Progeria patients, which are characterized by accelerated aging, and patient cells with systemic sclerosis, which show a more normal aging process, as well as from young healthy and young subjects.
Pontus Nordenfelt	Lund University	Broadly protective anti-M antibodies as treatment against group A streptococcal infection	Medicine	2024	Amount granted: SEK 600 000 Group A Streptococcus is one of the bacteria that causes most illness and can also lead to death. There is a lack of both vaccines and appropriate treatments for serious conditions such as sepsis, where antibiotics may not be enough to save lives. Antibodies have been shown to be an effective treatment for other pathogens, but there are none for group A streptococcus, where one problem is the large number of bacterial variants. We have recently discovered a broadly protective monoclonal antibody against group A streptococcus, which we have raised from patients who have undergone infection. It is the first broadly protective antibody to be described. The fact that the antibodies are of human origin increases both safety and the chance that they can work as a treatment. We now want to develop some more broadly protective antibodies to create a clinical cocktail treatment. We have internationally leading methods available from ex vivo discovery, in vitro characterization and in vivo animal models. We see great clinical opportunities. Polyclonal antibody therapy has been tried, but the antibodies involved are not known, with unclear effects. Instead, we plan to put together well-characterized monoclonal antibodies as cocktails, where we also have the opportunity to improve properties through antibody design, something we have shown with our first antibody. As a combination therapy, it will be easy to administer with current antibiotic treatments for severe streptococcal infections.
Susanna Törnroth-Horsefield	Lund University	Disposal in the CNS - AQP4 as a drug target in neurodegenerative disease	Medicine	2024	Amount granted: SEK 550 000 The water channel aquaporin 4 (AQP4) is central to the water balance in the brain. AQP4 is mainly found in astrocytes, one of the brain's supporting cells, where it is concentrated in the end-feet of cells surrounding the brain's blood vessels. This is crucial for creating a flow through the brain that helps clear away debris. This flow increases when we sleep and decreases sharply as we age, leading to increased susceptibility to neurodegenerative diseases. AQP4 has therefore been identified as a promising drug target for the development of new treatments for diseases such as Alzheimer's and Parkinson's, but also for brain edema and epilepsy, for example. We have recently characterized how AQP4 is regulated and shown that inhibition of this mechanism by drugs can be used to treat brain edema in rats. This project builds on this important discovery and aims to further our understanding of AQP4 regulation and create protein models that can be used in drug design. To do this, we will study how AQP4 binds to two proteins, calmodulin and alpha-syntrophin, and determine the structure of the protein complexes. We will then use these models to identify potential drug molecules and antibodies that affect the ability to interact. The results will provide crucial information on the role of AQP4 in the brain and provide the opportunity to develop new revolutionary treatment strategies for neurodegenerative diseases.
Hans Ellegren	Kungl. Academy of Sciences	Torsten Söderberg Academy Professorship in Medicine 2024	Medicine	2023	Amount awarded: SEK 10 000 000 There is a great need for this type of research position, where outstanding professors are given the opportunity to further develop their research. It is an important part of further strengthening Swedish research in the light of international developments. The professorship will promote internationally leading research in the field of medicine by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed on the basis of documented scientific quality of the research performed. Particular emphasis will be placed on research carried out during the last five-year period. The quality of the research program, the degree of innovation and the importance for the development of medical research will also be assessed. The grant will be used to fill a new five-year Academy Professorship in Medicine in 2024.
Pierre Hakizimana	Linköping University	Artificial Intelligence-driven approaches for therapeutic prevention of hearing loss	Medicine	2023	Amount granted: SEK 800 000 More than 400 million people globally suffer from hearing loss, resulting in costs of almost USD 980 billion annually. In addition to impairing hearing, it also reduces quality of life and can lead to depression, dementia and learning disabilities. Particularly vulnerable are over a billion young adults and teenagers who are regularly exposed to harmful noise levels, as well as soldiers in noisy combat zones. Despite current hearing protection, they are still at risk. With increasing tensions at EU borders, such as in Ukraine, and military activities such as Sweden's Aurora 23, hearing protection is now more than ever a priority in both healthcare and national security. Previous research methods, which tried to combat harmful molecules released after noise exposure, proved insufficient. Instead, we need to act earlier to prevent permanent hearing damage. My recent discoveries using AI technology show early signs of hearing damage and point out specific vulnerable parts of the ear. Based on these insights, I propose to use established drugs, such as aspirin and streptomycin, as protection against these damages. First results, especially with streptomycin, are promising. The aim of the project is to use existing drugs to prevent hearing damage from becoming permanent. With the right research and technology, we hope to protect millions from the silent threat of hearing loss.
Lars L Gustafsson	Karolinska Institute	History of science study of Sune Bergström: legendary scientist, leader and social reformer	Medicine	2022	Amount granted: SEK 150 000 Researchers whose discoveries contribute to health attract interest. Nobel Prize winner Sune Bergström (1916-2004) was an influential Swedish medical researcher in the 20th century, but he has no biography. This project aims to fill this gap. We highlight how Bergström and his colleagues became successful and describe his life, work and importance based on interviews, archival research and literature. This is presented in a biography in Swedish and English. Part I describes the researcher and private person Sune Bergström from his school years in the USA during the burning world war, groundbreaking discoveries about prostaglandins and his time as a professor at the age of 31 in Lund and in Stockholm from 1959. Part two highlights his commitment to global health and his industrial collaborations. Part three is about the communicator, mentor and research leader and analyzes his leadership style and good contacts with national and global leaders and authorities, such as the WHO (World Health Organization) and the NIH (National Institutes of Health) in the US. Project leaders Gustafsson and Tjärnlund have extensive experience in research, archival studies and research communication. We are applying for funding to complete the project, which has so far conducted around 50 interviews with key individuals and collected material from 15 different archives. The biography is expected to be completed in 2024. The visionary Sune Bergström, his actions and driving forces can illustrate how research contributes to improved health for millions of people.
Robin Fåhraeus	Umeå University	Developing treatment for Epstein-Barr virus-related diseases.	Medicine	2022	Amount granted: SEK 500 000 Epstein-Barr virus (EBV) causes various diseases and it has been estimated that 2-3% of all cancers are caused by EBV. Other diseases include infectious mononucleosis. More recently, an association between EBV and multiple sclerosis has been demonstrated. Despite knowing that EBV causes disease for 60 years, there is no specific treatment for EBV. All EBV-infected cells express the protein EBNA1, which is essential for the virus, and knocking out EBNA1 also knocks out the virus. EBNA1 is therefore an interesting protein for the development of new treatment methods against EBV. Our research has shown that EBNA1 has a unique mechanism for regulating its own synthesis. We have shown the cellular mechanisms that regulate EBNA1 synthesis and we have identified compounds that specifically inhibit EBNA1 synthesis. We have also shown how these compounds work. Nasopharyngeal cancer (NPC) is a tumor that carries the virus in 100% of all cases. Treatment of two different NPC tumors in mice with anti-EBNA1 substances does not affect the animals significantly and there are no signs of toxicity but the tumors disappear. Substances that are more effective in inhibiting EBNA1 are more effective in preventing NPC tumor growth. A tumor that does not carry EBV (melanoma) is not affected by the treatment. This project aims to develop, in collaboration with medicinal chemists, new compounds that are effective in inhibiting EBNA1 synthesis and can be developed into drugs for EBV-associated diseases.
Hans Ellegren	The Royal Swedish Academy of Sciences	Torsten Söderberg Academy Professorship in Medicine 2023	Medicine	2022	Amount awarded: SEK 10 300 000
Susanne Bejerot	Region Örebro County	Rituximab - a placebo-controlled trial for schizophrenia spectrum disorder	Medicine	2022	Amount granted: SEK 3 324 240 85% of those with schizophrenia never recover. They also have an increased morbidity in physical diseases, especially immunological ones. In recent years, several studies have demonstrated a link between inflammation/autoimmunity and schizophrenia. Between 2019-2022, we have investigated in an open pilot study whether nine severely ill therapy-resistant patients with schizophrenia spectrum disorder improve with the anti-inflammatory drug rituximab. Rituximab is a well-proven drug (anti-CD20 antibodies) commonly used in MS and rheumatoid arthritis. Treatment is given every six months. Rituximab has not previously been tested in mental illness so our pilot study is groundbreaking. We have seen very good results in several patients with SSD (6/9), so we intend to proceed with a placebo-controlled study in 104 patients (18-51 years). Rituximab is given as a single drop. Serious side effects can occur, but are extremely rare. The study patients continue with their regular drug treatment which reduces the risk of deterioration. We will evaluate the effect after 12 weeks using established evaluation instruments and examine general improvement, function and self-rated health. Patients will be followed for 6 months. Side effects and signs of inflammation will be investigated. If the treatment proves effective, it will most likely revolutionize the understanding and treatment recommendations for a severely affected patient group.
Anders Olofsson	Umeå University	A new form of therapeutic and prophylactic treatment for transthyretin amyloidosis	Medicine	2022	Amount granted: SEK 584 616 Summary will be published shortly
Stina Wickström	Karolinska Institute	Cell therapy with Tumor Infiltrating Lymphocytes (TIL) and Dendritic Cell vaccine.	Medicine	2022	Amount granted: SEK 1 000 000 With several breakthroughs in immunology research, we are on the verge of a new generation of cancer treatments based on activating the body's own immune system to resist the cancer. Immunotherapy with immune-activating antibodies can prolong survival in patients with certain types of severe cancer but only works in a small proportion (<30 %) av patienter, varför det behövs andra behandlingsalternativ. Cellterapi är ett exempel på en lovande ny behandlingsmetod, där patientens egna vita blodkroppar aktiveras utanför kroppen och ges tillbaka till patienten för att där bekämpa cancerceller.Vi har lovande resultat där vi behandlar patienter med den elakartade hudcancern malignt melanom med cellterapi kombinerat med ett tumörvaccin. Vita blodkroppar (T-celler ) renas fram från cancertumören, mångfaldigas och ges tillbaka i ett stort antal till patienten för att söka upp och döda tumörceller. Behandlingen kombineras med ett tumörvaccin, för att öka effekten av de injicerade vita blodkropparna. Hos de patienter som erhållit behandling har en tydlig effekt på dennes cancer uppmätts, och 3 av dessa patienter är fortfarande fria från sjukdom många år efter behandlingen. Vi har nu tillstånd från att behandla ytterligare 10 patienter och vill även utöka till senare behandla även andra typer av cancer. Målsättningen är att kunna erbjuda cancerpatienter en effektiv immunterapi med hjälp av cellterapi och tumörvaccin.
Hjalmar Brismar	Royal Institute of Technology	Automated quantitative optical renal pathology	Medicine	2021	Amount granted: SEK 1 558 152 The number of people with kidney disease worldwide amounted to nearly 700 million in 2017. This number is expected to increase in the coming years unless investments are made in improved diagnostics, new treatment methods and preventive measures. Kidney diagnostics currently use a combination of urine and blood tests and microscopic analysis of kidney tissue (biopsies). The microscopy methods are several decades old and are based on cutting the tissue into thin/ultra-thin sections and visualizing disease morphology on a large and small scale. Light microscopy has been used since the 1880s to visualize stained larger kidney structures. To visualize the smallest filter structures in the kidney, electron microscopy has been used since the 1950s. Since 2015, we have developed new methods that make it possible for the first time to image these ultra-small structures also with light microscopy. We have shown that we can see nanometer-sized filtration structures in three dimensions in whole tissue samples. Our optical pathology enables a fully automated and quantitative description of pathological changes in the kidney on a small and large scale. In this project, our methods are further developed on human tissue for clinical diagnosis of kidney diseases in collaboration with renal clinics and renal pathologists. We will further apply automatic image analysis with deep learning to more quickly, efficiently and easily diagnose kidney diseases with our optical renal pathology method.
Göran K. Hansson	Kungl. Academy of Sciences	Torsten Söderberg Academy Professorship in Medicine 2022	Medicine	2021	Amount awarded: SEK 10 300 000 There is a great need for this type of research position, where proven outstanding professors are given the opportunity to further strengthen and develop their research. The professorship will promote internationally leading research in the medical field by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed based on the documented scientific quality of the research carried out. Particular emphasis will be placed on research carried out during the last five-year period. The quality of the research programme, the degree of innovation and the importance for the development of medical research will also be assessed. The Academy is therefore applying for an additional grant of SEK 10 million so that a five-year Academy Professorship in Medicine can be filled in 2022.
Pär Hallberg	Uppsala University	SWEDEGENE - genetic causes of adverse drug reactions	Medicine	2021	Amount granted: SEK 1 112 686 Adverse drug reactions are a common cause of morbidity and death. The total cost amounts annually to 10% of the Swedish healthcare budget. There is therefore much to be gained by using precision medicine to identify the most appropriate drug for the individual patient using genetic testing. Currently, knowledge of the genetic causes of adverse drug reactions is limited. The research initiative SWEDEGENE, for which the main applicant is the project leader, has changed the conditions and provides good opportunities for studies in this area. At present, SWEDEGENE has collected DNA and clinical data for about 3200 patients who have suffered about 40 different types of adverse drug reactions. The first results of the project have identified several clinically relevant associations between side effects and genetic variation. At present, there are results from whole genome scans for 2300 patients and for 1,000 individuals also from whole genome sequencing. The purpose of the project is to process and report the collected data generated by the research initiative.
Agneta Nordenskjöld	Karolinska Institute	Female clerks in Sweden in the second half of the 19th century	Medicine	2021	Amount granted: SEK 150 000 Field surgeons have been described since the 15th century in Sweden and were responsible for surgical care during wars and could then also carry out their activities in civilian life during peacetime. In 1861, a new regulation on the profession of field surgeon was issued regarding the treatments that field surgeons were allowed to perform, mainly minor surgery, and the regulation included that women could also become field surgeons. The first female medical officer in Sweden was originally a midwife, and she was examined before the Board of Health in 1863. During the period 1860 to 1930, according to the census, there were around 30 female medical officers. Field nurse training was later abolished in 1896 by a parliamentary decision, but field nurses were active in Sweden well into the 20th century. This project aims to describe the number, education, activities and tasks of female field clerks in Sweden. We have so far identified 70 female clerks in Sweden through various sources. Data has been compiled regarding their demographic information, year of graduation, location and period of activity, as well as references. The project will, with the help of searches in the National Archives, mainly concerning the Karolinska Institute, the Medical Board and the Collegium medicum, and in the City Archives, concerning the archives of the 1st city doctor, also describe education, work tasks and the demarcation with other professional groups.
Marie Wahren-Herlenius	Karolinska Institute	Translational studies on congenital heart block for mortality reduction	Medicine	2020	Amount granted: SEK 1 000 000 Congenital heart block can develop in the fetus during pregnancy in a woman with SSA and SSB autoantibodies. International studies report a mortality rate of 25-30%. Through our clinical and molecular studies, we have established a surveillance program in which we observe less than 4% mortality, as well as a significantly increased time after birth to pacemaker need in the child. However, in the majority of SSA/SSB positive pregnancies no heart block develops - and almost half of all blocks develop in pregnancies where the woman is not known to carry SSA/SSB antibodies. The aim of this project is to identify biomarkers to identify the high-risk pregnancies and monitoring methodology so that the program can be made available to all at-risk pregnancies. We will use a world-unique biobank of samples collected over a 15-year period to identify clinically useful markers using proteomic methodology. Screening methods to identify at-risk pregnancies in large groups will be developed using immunological techniques. Reducing the mortality rate for a disease to a quarter is a breakthrough that we now want to make available to the wider population and the world.
Sven-Erik Dahlén	Karolinska Institute	3-COMBO: New strategy to treat asthma in young children and adults by broadly blocking mast cells	Medicine	2020	Amount granted: SEK 2 000 000 The aim of the project is to conduct a proof of concept study of a new and previously untested strategy to treat asthma. We have shown in animal experiments and in isolated human airways that a combination of three different drugs can fully protect the airways against asthmatic airway narrowing. The antagonists block three groups of mast cell signaling molecules: histamine, prostaglandins and leukotrienes. We have also shown in clinical trials in asthmatics that when two of these drugs (antihistamine and leukotriene antagonist) are combined, partial protection against allergen-induced airway narrowing is obtained. Our hypothesis is that the pretreatment that has been experimentally shown to be effective will also fully protect allergic asthmatics against the standardized asthma attack obtained during controlled exposure to allergens, so-called allergen provocation. In the trial, asthmatics will be pre-treated in a randomized order with placebo, or various combinations of the active substances montelukast (registered leukotriene antagonist), desloratadine (registered antihistamine), and ramatroban (prostaglandin antagonist that will be imported from Japan where it is used for hay fever). Ramatroban blocks the receptors for prostaglandins that are suspected to be involved in asthma. The project is testing a Swedish basic research discovery with the potential to create a new future low-cost alternative for tablet treatment of asthma.
Lennart Lindbom	Karolinska Institute	New approach to counteract vascular leakage in severe infectious conditions	Medicine	2020	Amount granted: SEK 365 000 Local infections in the body can spread to the blood and cause sepsis. Sepsis is a serious condition that often leads to tissue damage in several major organ systems with high mortality rates. The body's immune system plays an important role in containing the infection, but at the same time causes damage to the blood vessels of tissues, resulting in plasma leakage. The blood vessels of the lungs are particularly vulnerable, leading to pulmonary edema and severe respiratory failure. A similar process has been observed in patients with severe Covid-19 disease in the current coronavirus pandemic. We have previously shown that proteins released from the storage vesicles of a group of white blood cells (neutrophil granulocytes) are strongly involved in reducing the barrier function of blood vessels during inflammation. We have also found that the harmful effect of these proteins on blood vessel permeability can be effectively counteracted by treatment with the heparin-like substance sevuparin. In the current project, we want to establish the therapeutic value of sevuparin treatment in severe infectious conditions. Blood plasma from sepsis and Covid-19 patients is analyzed for proteins that induce increased vascular permeability and edema formation, and the ability of sevuparin to inactivate these substances is evaluated. The results from these analyses will form the basis for planned clinical trials with sevuparin in severe infections.
Greta Hultqvist	Uppsala University	Protein drug design for improved drug delivery and increased therapeutic efficacy	Medicine	2020	Amount granted: SEK 2 000 000 Immunotherapy is one of the most promising treatment strategies for Alzheimer's disease despite the fact that large molecules, such as the antibodies used, are kept out of the brain by the blood-brain barrier. We have developed a core transporter protein that increases the uptake of antibodies in the mouse brain by almost 100 times and now want to continue our work on these projects in the following two steps: 1. transport into the human brain. Our brain transporter does not work in humans. There are viruses that infect the brain in both mice and humans. In order to do so, they must first cross the blood-brain barrier, so they have developed proteins on their surface that act as blood-brain barrier transporters. In this project, we will test whether these can be used to transport antibodies into the brain. 2. increase the brain's own degradation of amyloid beta. The treatment methods currently in clinical trials target the aggregates that have already been formed and do not bind to the smallest aggregates, which are perhaps the most toxic. If you can increase the brain's degradation of amyloid beta, you can prevent the aggregates from forming at all and then have a major effect on cognition. In this project, we try to activate the endogenous degradation by transporting the peptide somatostatin into the brain with our BBB transporter. There is enormous potential for improvement in immunotherapy and diagnostics of Alzheimer's disease and other brain diseases if we can significantly increase the uptake of antibodies in the brain and target new types of aggregates.
Lars L. Gustafsson	Karolinska Institute	History of science study of Sune Bergström: legendary scientist, leader and social reformer	Medicine	2020	Amount granted: SEK 150 000 In the 20th century, research breakthroughs contributed to better public health. The question of which scientists make discoveries that develop society has interested people for many years. One of Sweden's greats is Nobel Prize winner and professor of medicine Sune Bergström (1916-2004). There is no biography of him, and this project aims to fill this gap. We will partly document Bergström's life, work, driving forces and significance and partly write a biography of him in Swedish and English based on interviews, archive research and literature studies. Part I of the biography describes the researcher and private person Sune Bergström from his school years in the USA during the burning world war, the groundbreaking discoveries about prostaglandins and the time as a professor at the age of 31 in Lund and in Stockholm from 1959. Part two highlights Bergström's commitment to global health in poor countries and his capacity for industrial collaboration. Part three describes Bergström, the communicator and mentor, and his leadership style with a brilliant ability to gain support for research and education initiatives. The biography is scheduled for completion in the first half of 2022. The visionary Sune Bergström, his achievements and driving forces can illustrate how research and international cooperation improve the health of millions of people.
Artur Schmidtchen	Lund University	Studies on SARS CoV-2 Spike protein and its effect on inflammation	Medicine	2020	Amount granted: SEK 1 135 000 COVID-19 patients may develop excessive and uncontrolled inflammation causing a dysfunctional inflammatory state, characterized by severe organ damage with acute respiratory distress syndrome (ARDS) as a common denominator. Cardiovascular diseases, high blood pressure and diabetes, as components of Metabolic Syndrome (MS), appear to play an important role in developing a more severe form of the disease. Apart from the clinical link that MS is a risk factor for COVID-19, mechanistic information on the link between MS and COVID-19 is lacking. However, there is a well-known link between high levels of lipopolysaccharide (LPS) and MS. We have made the unexpected but significant discovery that the extracellular protein in SARS Cov2, the Spike protein (S) interacts with and strongly boosts the inflammatory response to LPS. In this project, we aim to analyze the interaction between S and LPS and the effects on inflammation. For this we will use in silico models, biophysical and biochemical methods in combination with studies in cell systems, human blood and animal models. The results, which will be communicated immediately after the completion of the proposed project, will provide a possible molecular explanation for the association between COVID-19 and MS and may lead to new therapeutic targets and strategies to ameliorate the hyperinflammation observed in COVID-19 patients.
Claes Ohlsson	University of Gothenburg	A new mechanism for regulating body weight	Medicine	2020	Amount granted: SEK 1 500 000 Obesity is a growing public health problem worldwide, with more than one billion people overweight and 300 million obese. Obesity contributes to serious diseases such as diabetes and cardiovascular disease. Several reports have shown that people who spend much of the day sitting have an increased risk of obesity and diabetes. Our results suggest that increased loading on the legs, which occurs when standing up, may lead to increased activation of a 'body wave' in the weight-bearing long tubular bones is activated more, and that this in turn leads to more activity in an anti-obesity system and hence reduced weight. There is already a well-known system that aims to keep fat mass constant. The anti-obesity hormone hormone leptin is released into the bloodstream from adipose tissue in proportion to the size of the fat mass. Leptin exerts a negative feedback in the brain leading to reduced appetite and obesity. Unfortunately, most obese people are, for unknown reasons, insensitive to the leptin's anti-obesity effect. We have now shown in the prestigious American Academy of Sciences journal PNAS that the insertion of weights in the abdominal cavity or under the skin of obese mice leads to a reduction in food intake, body weight and fat mass decrease independently of leptin. This effect appears to involve a specific cell type in the long tubular bones. We now want to to study the exact mechanism of how the 'body wave' in the legs affects fat mass and appetite, probably via an effect on the on the brain. We also want to investigate the importance of this novel system for fat regulation in humans.
Nilsson, Per	Karolinska Institute	Autophagy as potential treatment for Alzheimer's tau pathology	Medicine	2019	Amount granted: SEK 1 000 000 Alzheimer's disease affects 100 000 people in Sweden. There is no cure and the need is great. The disease is caused by the accumulation of the protein tau in neurons in the brain, which causes the cells to die. In addition, the cell's cleaning machinery - autophagy - is disrupted. Our hypothesis is that it is precisely the defective autophagy that causes the accumulation of tau. This project is about finding out if this is true by removing the autophagy function in mice with tau pathology and seeing if the pathology gets worse. As a therapy, we will try to see if increasing autophagy in brain cells has a positive effect and improves tau pathology. This has never been investigated in vivo before and we hope to contribute to the understanding of Alzheimer's.
Eriksson, Maria	Karolinska Institute	Base editing as a treatment for Hutchinson-Gilford progeria syndrome	Medicine	2019	Amount granted: SEK 1 000 000 The Hutchinson-Gilford Progeria Syndrome (progeria) is a very rare genetic disorder, which is almost exclusively (>95% of cases) caused by a specific mutation in the lamin A gene, LMNA c.1824C>T. This mutation leads to the expression of a defective lamin A protein in the cell called progerin. Children with progeria show symptoms of early ageing and die in adolescence due to cardiovascular disease. Progerin is also expressed in the tissues of people who do not have progeria and levels have been shown to increase with age. The underlying mechanisms of how progerin leads to the disease symptoms are still unclear. Despite this, more than a dozen different treatment strategies have been developed with several resulting in clinical trials in patients. However, the treatments have been disappointing with limited success in patients. Here we propose so-called adenine base editing as a possible therapeutic strategy for progeria. Base editing has the potential to correct hereditary diseases by eliminating the disease-causing mutation and the possibility of a permanent cure. The technology is based on a modification of the CRISPR/Cas9 system and enables direct transformation of a DNA base without the introduction of double-stranded DNA breaks with low non-specific editing. Our preliminary studies from treatment of cells from progeria patients and a tissue-specific mouse model have shown positive results. In the planned study, we hope to confirm and further substantiate these results.
Sehlin, Day	Uppsala University	Bispecific antibodies for the treatment of neurodegenerative diseases	Medicine	2019	Amount granted: SEK 1 000 000 Neurodegenerative diseases such as Alzheimer's and Parkinson's currently lack effective treatment. The most promising strategy is immunotherapy, where antibodies are administered to neutralize the proteins amyloid-β (Aβ) that clump together and form plaques in Alzheimer's disease and alpha-synuclein (α-syn) that forms so-called Lewy bodies in Parkinson's disease. Our previously developed antibody mAb158 is selective for protofibrils, a toxic precursor of the Aβ plaque, and its humanized form (BAN2401) has shown positive results in a large clinical trial involving 856 Alzheimer's patients. We have developed similar antibodies for α-syn. However, antibodies are large molecules that have difficulty entering the brain, so high doses must be administered to achieve an effect. To increase brain uptake and thus the treatment effect, mAb158 has been linked to 8D3, an antibody that binds to the transferrin receptor, normally involved in the transport of iron. Like a Trojan horse, 8D3 then carries mAb158 into the brain, where it can neutralize the toxic protofibrils. Using imaging techniques, we have shown that this strategy leads to greatly enhanced antibody uptake in the brains of mice. With this project, we want to conduct therapy studies with modified antibodies against both Aβ and α-syn in transgenic mice, comparing its effect with unmodified antibody and studying treatment mechanisms. We believe that this new treatment strategy is a prerequisite for achieving effective immunotherapy in brain diseases.
Borén, Jan	University of Gothenburg	Small-molecule inhibitor to prevent liver obesity - our fastest growing public disease	Medicine	2019	Amount granted: SEK 1 000 000 Today, more than half of the Swedish population is overweight or obese. Previously, it was thought that it was increased fatty tissue that was dangerous. Now we know that it is more important where the fat is stored. When fat tissue cannot store more fat, it is stored in other tissues such as the liver, heart and muscles. Non-alcoholic fatty liver disease (NAFLD) has been increasing rapidly. Today, 20-25% of the population has the disease and among patients with obesity and type 2 diabetes the figure is 70-90%. Patients with NAFLD live on average 5 years less. They are mainly affected by cardiovascular diseases, but liver-related mortality is also increasing. This is because around 20% of patients develop liver inflammation and liver fibrosis. This condition is called non-alcoholic steatohepatitis (NASH). Patients with NASH are at greatly increased risk of developing cirrhosis and liver cancer. There are still no approved drugs for NAFLD/NASH. Our project is based on a novel concept, whereby systems biology analyses identify target molecules, and then we develop small molecules that can inhibit or activate these target molecules. In cell culture and animal experiments, we test whether they can reduce fat accumulation and fibrotization in liver cells. Through an iterative process, we improve our small molecule drug candidates. The research team combines complementary skills and we have already generated results that demonstrate the success of the research strategy.
Bejerot, Susanne	Örebro University Hospital	Rituximab: Immunotherapy for treatment-resistant severe mental illness. Pilot and multicenter study	Medicine	2019	Amount granted: SEK 1 000 000 Schizophrenia and obsessive-compulsive disorder (OCD) affect ~3% of the population. The illnesses often begin in adolescence. Approximately 1/3 of patients are treatment-resistant, i.e. no known treatment is effective. These people have extremely low function, quality of life and a shortened life. Family members are also severely affected. Patients also have a higher incidence of physical diseases, especially autoimmune ones. While immunological diseases are traditionally associated with physical illness, recent research has shown that mental illness can also be explained by inflammation in the brain. Rituximab is a well-proven anti-inflammatory drug used in several autoimmune diseases. It consists of antibodies that block the function of a type of cell (B cells) that is part of the body's immune system. It inhibits the immune system. We will investigate whether severely ill and treatment-resistant adults with schizophrenia or OCD improve with rituximab. The treatment will take place on one occasion, then participants will be followed regularly for one year to evaluate the effect. The evaluations will be done using established evaluation instruments. We will also examine signs of inflammation in blood, spinal fluid, feces and brain (using brain imaging) before and after treatment to look for biological markers that can give us guidance on causality. If effective, treatment with rituximab could eventually revolutionize the understanding and treatment of these patient groups.
Nilsson, Peter	Linköping University	New potential drugs for Alzheimer's disease	Medicine	2019	Amount granted: SEK 1 000 000 Neurodegenerative diseases, such as Alzheimer's disease, comprise some of our major public health problems and affect millions of people worldwide. Despite significant efforts, there is still a lack of effective drugs to prevent or cure these diseases. The aim of our project proposal is to investigate whether a particular type of molecule can be used to stop the progression of Alzheimer's disease. Step 1 when developing a drug is to choose a target to which the drug will be directed. The targets we have chosen are two proteins, A-beta and tau, which occur in various forms of deposits (aggregates) in the brain in Alzheimer's disease. Several studies have shown that these aggregates spread between nerve cells and that the aggregates affect the function of the cells, leading to nerve cell death. In the project, we will produce molecules that selectively find A-beta or tau aggregates and the molecules will then be tested in different fruit fly models to see how they affect the spread and induced cell death of A-beta and tau aggregates. The overall goal of the project is to show that tailored molecules can selectively affect the negative effects of A-beta and tau aggregates. In the long run, the progress of the project may lead to a new generation of drugs that could be used to prevent the underlying disease process in Alzheimer's disease and other similar neurodegenerative diseases.
Sotiriou, Georgios	Karolinska Institute	Photo-activated antimicrobial nanocoatings on medical devices	Medicine	2018	Amount granted: SEK 1 000 000
Ohlsson, Claes	University of Gothenburg	A new mechanism for regulating body weight	Medicine	2018	Amount granted: SEK 2 000 000 Obesity is a growing public health problem worldwide with more than one billion overweight and 300 million obese according to the WHO. Obesity contributes to serious diseases such as diabetes and cardiovascular disease. Several reports have shown that people who spend much of the day sitting are at increased risk of obesity and diabetes. Our results suggest that increased leg loading, which occurs when standing up, may lead to more activation of a 'body wave' in the weight-bearing long tubular bones, which in turn leads to more activity in an anti-obesity system and hence reduced weight. There is already a well-known system that aims to keep fat mass constant. The anti-obesity hormone leptin is released into the bloodstream from adipose tissue in proportion to the size of the fat mass. Leptin exerts a negative feedback loop in the brain leading to reduced appetite and obesity. Unfortunately, for unknown reasons, most obese people are insensitive to leptin's anti-obesity effect. We have now shown in the prestigious American Academy of Sciences journal PNAS that inserting weights into the abdominal cavity or under the skin of obese mice reduces their food intake, body weight and fat mass independently of leptin. This effect seems to involve a specific cell type in the long tubular bones. We now want to study the exact mechanism of how the 'body wave' in the legs affects fat mass and appetite, probably via an effect on the brain. We also want to investigate the importance of this novel system for fat regulation in humans.
		Cerebrospinal fluid flow and its role in Alzheimer's disease	Medicine	2018	Amount granted: SEK Neurodegenerative diseases are characterized by the accumulation of toxic molecules, often in the form of proteinaceous waste. The cerebrospinal fluid (CSF), which is mainly produced at night, has a great capacity to dispose of these toxic waste products from the brain. However, many aspects of the diurnal CSF variation in disease, dietary modulators of CSF, and the significance of CSF dynamics for disease progression are poorly characterized. In this project, we will investigate CSF production volume and flow rate in the context of Alzheimer's disease (AD). We will recruit participants from several, including: AD patients, the patient with mild cognitive impairment (MCI), elderly controls, and young controls. All participants will undergo a non-invasive phase contrast MRI in a state-of-the-art 7T MRI system to measure CSF production volume and flow rate. Furthermore, using different modalities of MRI scans, we wish to evaluate how these parameters are affected by the consumption of commonly used dietary products such as alcohol and caffeine, which have been shown to induce CSF movement in the brain. Finally, we want to determine whether there is a correlation between CSF production and cognitive abilities, and we will specifically investigate whether low CSF production is predictive of poorer prognosis.
Kiessling, Rolf	Karolinska Institute	Cell therapy for malignant melanoma with tumor-infiltrating lymphocytes and Dendritic cell vaccine	Medicine	2018	Amount granted: SEK 1 000 000 The aim of the project is to develop a new immunotherapy approach for the treatment of malignant melanoma, a malignant skin cancer. Immunotherapy, which aims to activate the body's immune system to eliminate cancer cells, has made great progress and treatment with immune-activating antibodies prolongs survival in patients with metastatic melanoma. However, a majority (70-80%) of patients do not respond to this treatment. Cell therapy with white blood cells produced from the patient's cancerous tumor, called tumor-infiltrating lymphocytes (TILs), which are then multiplied in large numbers and returned to the patient, has a very good effect on the disease. Tumor vaccination with a special type of immune-activating cells extracted from the patient's blood, called Dendritic Cells (DC), has also been shown to be effective against certain types of cancer. Design and methods: A clinical study, approved by the Swedish Medical Products Agency and Ethics Committee, is ongoing with the administration of TIL cells combined with Dendritic Cells (DC) vaccine to patients with advanced melanoma disease. Three of the four very seriously ill patients in the study that we treated with the combination of TIL and DC have responded very well with complete or almost complete regression of the cancer, even though they no longer respond to other types of cancer treatment. We will now be able to treat another 10 patients with this method, as well as to improve our methods for the production of high activity TIL and DC and to measure the effect immunologically.
Hansson, Göran K.	Kungl. Academy of Sciences	Torsten Söderberg Academy Chair in Medicine 2019	Medicine	2018	Amount granted: SEK 10 168 000 The Torsten Söderberg Foundation currently funds seven academic professorships in medicine at the level of SEK 2 million per year for five years. There is a great need for this type of research position, where proven outstanding professors are given the opportunity to further strengthen and develop their research. It is an important part of further strengthening Swedish research in the light of international developments. The professorship will promote internationally leading research in the medical field by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed based on the documented scientific quality of the research carried out. Particular emphasis is placed on research carried out during the last five-year period. The quality of the research program, the degree of innovation and the importance for the development of medical research will also be assessed.
Erlandsson, Anna	Uppsala University	Role of astrocytes in spreading amyloid-beta pathology	Medicine	2018	Amount granted: SEK 1 000 000 The overall goal of the project is to investigate how the brain's support cells, the astrocytes, contribute to Alzheimer's disease and how we can influence them with different treatments. Interesting results from our previous research show that astrocytes influence processes that can lead to the spread of the disease in the brain. With this new approach, we hope to identify future treatment strategies for Alzheimer's disease. More specifically, we will Investigate how astrocytes contribute to the spread of Alzheimer's disease pathology. Identify strategies to increase astrocyte degradation of amyloid-beta and thus limit the spread of the disease. Study how astrocytes are involved in the extensive nerve cell death in the brain in Alzheimer's disease. To study the role of astrocytes in the spread of Alzheimer's disease pathology, we will primarily use mouse and human cell cultures, but we will also perform complementary animal studies and analyze patient tissue. Currently, there is no drug treatment available to prevent nerve cell death in Alzheimer's disease or to limit the spread of the disease in the brain. Our results will provide important insights into the role of astrocytes in Alzheimer's disease and thus promote the development of new therapies.
Brodin, Petter	Karolinska Institute	Inflammatory complications in premature babies	Medicine	2018	Amount granted: SEK 1 000 000 Newborn babies have immature immune systems and an increased risk of infections, especially those born prematurely. Very preterm infants are also at risk of other complications such as necrotizing colitis (NEC), retinopathy (ROP) and chronic pulmonary disease (BPD), and all of these dreaded complications are inflammatory conditions involving the infant's immune system. At present, we do not fully understand the factors that give rise to these inflammatory conditions, nor can we predict with certainty which preterm infants will be affected. In this project, we conduct the most detailed mapping of the neonatal immune system to date in order to better understand the immunological processes associated with inflammation (NEC, ROP and BPD) and severe infections in preterm infants. Our goal is both to understand these processes better, but also to identify markers that can help us predict the risk of infection in a given preterm infant. In this way, we hope to optimize the care of preterm infants in the future with reduced risk of complications and increased survival in this vulnerable patient group.
Flower, Anna	Lund University	New treatments for infections based on pathogenic bacteria's strategies to escape the complement system	Medicine	2018	Amount granted: SEK 1 500 000 Our study focuses on clinically important bacterial pathogens, for which the ever-increasing antibiotic resistance requires new treatment options. Every successful pathogenic bacterium must defend itself against the complement system, a central part of the innate immune system. We have previously shown that many bacteria thus cover their surface with human complement inhibitors as a defense and we now want to investigate whether this property can be used for the development of new treatment with recombinant fusion proteins. These fusion proteins should prevent interactions with complement inhibitors while initiating complement attack on the bacterial surface. An advantage of the therapeutic use of these molecules is the low risk of resistance development, as the ability to bind complement inhibitors that our fusion proteins exploit provides a survival advantage. We will investigate whether our fusion proteins are effective against infections with Neisseria gonorrhoeae (a common STD) and gram-negative bacteria that infect burn wounds. Clinical isolates will be used to estimate the proportion of these infections that could be successfully treated with our fusion proteins.
Zierath, Juleen	Karolinska Institute	Identification of metabolically important factors secreted by muscles during exercise	Medicine	2017	Amount granted: SEK 1 500 000 Type 2 diabetes is caused by a strong resistance to the hormone insulin in the body's tissues and a reduced production of insulin in the pancreas. Exercise affects the muscles, increasing insulin sensitivity and preventing the onset of type 2 diabetes. However, exercise has effects on almost every organ in the body through the need to adapt them to the increased mechanical, metabolic and thermoregulatory demands of increased body work. Skeletal muscles are known to secrete specific proteins, called myokines, to communicate this to other organs including the adipose tissue. This project focuses on systematically identifying factors that are secreted by muscles during exercise and that are important for increased metabolism in the body. These factors can be proteins but also other substances such as various metabolites. By combining cellular models of exercise with organ models (intact muscles) and with serum from humans (both healthy and type 2 diabetes patients) who have undergone short exercise sessions, we will be able to identify factors that are important in humans and in type 2 diabetes. Ultimately, these factors may form the basis for new biomarkers of response to exercise and new treatments for type 2 diabetes.
Wahlgren, Mats	Karolinska Institute	Unknown epitopes and cause of disease	Medicine	2017	Amount granted: SEK 1 000 000 Here we propose to create an intelligent set of randomly selected "disease structures" (peptides) to identify mainly tertiary and quaternary epitopes seen by the human immune system. The binding of immunoglobulins to peptides depends on its shape and charge, not the amino acid sequence, which likely allows us to also detect unknown antigenic carbohydrates and lipids. We have recently studied randomly generated peptides in silico for theoretical antigenicity based on previously identified B-cell epitopes. This was done by creating a new mathematical formula that applies the "Markov" and "Yen's K-shortest path" algorithms We can thus screen and rank an "infinite" number of peptides for theoretical reactivity but have started with a subset (10-6). In the first round we have studied 172,943 synthetic peptides for practical reasons as they fit on an array grid. In preliminary experiments, we have screened human sera from patients with 'discrete and defined' neurological disorders, such as obsessive compulsive disorder or amyotrophic lateral sclerosis and identified novel and uniquely reactive sequences. We now propose to develop diagnostic assays to study these and other diseases where the causes are unknown together with experts in the field. In later stages, this should lead to an increasing understanding of the origin and prevention of the diseases.
Pekny, Milos	University of Gothenburg	Astrocytes - a new target for CNS regeneration in stroke and ALS	Medicine	2017	Amount granted: SEK 2 300 000 During human ageing and in diseases and injuries affecting the brain and spinal cord, such as stroke and ALS (amyotrophic lateral sclerosis), cells in the brain and spinal cord die, leading to disability. We have found that astrocytes are key to slowing or even reversing this process. When neurons are damaged as a result of disease, astrocytes are activated and focus on minimizing and limiting the damage, especially in the acute phase after a brain injury. However, highly activated astrocytes, which form a scar of cells, can prevent the return of function in the long term by, among other things, inhibiting the formation of new connections between neurons. In transgenic mice, we have now managed to avoid harmful scarring and thus new connections have been formed between the remaining cells. The goal of this project is to pharmacologically control astrocyte activation and thus improve recovery after stroke. In preliminary studies, we have thus been able to slow down the course of the disease in mice with ALS. Increased knowledge of astrocyte activation and pharmacological control of their function offers great opportunities to develop new treatments for stroke and for neurodegenerative diseases.
Mahlapuu, Margit	University of Gothenburg	Molecular mechanisms and new treatment strategies for type 2 diabetes	Medicine	2017	Amount granted: SEK 1 000 000 The prevalence of type 2 diabetes (T2D) is increasing dramatically and T2D has become one of the major global health threats. Intensive research over the last decade has shown that ectopic lipid storage outside the adipose tissue, particularly in the liver and skeletal muscle, actively contributes to the development of insulin resistance, which in turn leads to T2D. Understanding the molecular mechanisms that control the storage of ectopic fat is therefore of paramount importance in order to find novel approaches that effectively prevent the occurrence, as well as improve the treatment, of T2D. Our latest research in extensive patient material, human cells and unique animal models has shown that the kinase STK25 is a new key regulator of lipid metabolism. Our studies show that STK25 binds to lipid droplets inside the liver cell and controls lipid accumulation and inflammation in the liver, and regulates the body's insulin sensitivity. Furthermore, we have identified selective and potent pharmacological inhibitors of STK25, which could potentially lead to a new unique treatment for T2D. The aim of the project is to map the molecular mechanisms that regulate lipid storage and the development of insulin resistance in the liver, focusing on STK25. The study contributes to the understanding of the complex and integrated signaling pathways that regulate insulin sensitivity and the changes that lead to T2D. The project may also form the basis for the development of new treatments for T2D and related metabolic diseases, based on pharmacological inhibitors of STK25.
Ingelsson, Martin	Uppsala University	Development of antibody-based immunotherapy for Parkinson's disease	Medicine	2017	Amount granted: SEK 1 487 000 In Parkinson's disease, alpha-synuclein accumulates in brain neurons and medium-sized forms of this protein, known as oligomers, are particularly harmful. We have produced antibodies against oligomers and shown in a mouse model that, after injection into the peritoneal cavity, these can be transported to the brain and reduce the amount of harmful alpha-synuclein and also reduce the risk of severe late motor disorders. In one study, we have shown that mice show subtle gait and behavioral disturbances as early as two to four months of age. In an ongoing study, we are therefore investigating whether these early symptoms can also be prevented with antibodies. The treatment will be completed in January 2018, followed by a series of brain tissue analyses. In addition to this study, we are mapping another mouse model and investigating whether we can get even better effects by using a harmless virus that allows antibodies to form directly in the neurons. Preliminary data suggests that treated mice get high levels of antibodies in the neurons and we are now planning a larger study to see if this strategy can also reduce pathology and symptoms in the mice. This research program represents important steps in the development of new treatment strategies for Parkinson's disease. We believe the prospects are realistic. Immunotherapy for Alzheimer's disease is being tested clinically, including with an antibody developed by the research group. The project is led by Professor Martin Ingelsson and will be carried out at Uppsala University in 2017-2019.
Hökfelt, Tomas	Karolinska Institute	Brain's galanin and substance P systems are altered in depression: Opening for new treatment	Medicine	2017	Amount granted: SEK 1 000 000 Depression is a life-threatening (suicide), common and costly disease (affecting 300 million people worldwide, costing a staggering €380 billion in the EU). Unfortunately, current treatments such as Prozac do not help in many cases. We want to develop new drugs based on neuropeptide antagonists by studying the postmortem brains of people suffering from depression. There are >100 neuropeptides with even more receptors (the same type as many current drugs). The focus is on the neuropeptides galanin and substance P, both of which play a role in depression-like behavior in laboratory animals. Our question is: does this also apply to humans? After all, medicines for humans should be developed through human studies. We have shown changes in the 'galanin genes' in patients with depression, and also seen differences in the galanin system in the brains of deceased people with depression (suicide). We now want to see if similar changes exist in the substance P system and also in other peptides (84 to be scanned). Preliminary findings show substance P changes, in areas that control emotions. We also want to use microscopic techniques to study in which brain cells these changes occur, and search for neuropeptide-related biomarkers of depression in the blood. Our results suggest that galanin antagonists are potential antidepressants and that substance P antagonists should be further investigated. Finally, we hope to diagnose certain types of depression using peptide markers in blood samples.
Hansson, Göran K.	Kungl. Academy of Sciences	Torsten Söderberg Academy Chair in Medicine 2018	Medicine	2017	Amount awarded: SEK 10 100 000 The Torsten Söderberg Foundation currently funds six academic professorships in medicine (the latest of which is in the process of being filled) at the level of SEK 2 million per year for five years. There is a great need for this type of research position, where proven outstanding professors are given the opportunity to further strengthen and develop their research. It is an important part of further strengthening Swedish research in the light of international developments. The professorship will promote internationally leading research in the medical field by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed based on the documented scientific quality of the research carried out. Particular emphasis will be placed on research carried out during the last five-year period. The quality of the research program, the degree of innovation and the impact on the development of medical research will also be assessed. The Academy is therefore requesting an additional grant of SEK 10 million to enable a five-year Academy Chair in Medicine to be established in 2018.
Collin, Mattias	Lund University	Streptococcal modification of antibody glycosylation in severe infections	Medicine	2017	Amount granted: SEK 700 000 Most proteins in our immune system are glycoproteins where carbohydrates (glycans) influence function. Antibodies are central to our acquired immune system and glycans are very important for their proper interaction with white blood cells. Not surprisingly, bacteria have evolved enzymes (glycosidases) that destroy or alter these glycans. We have discovered the first enzyme, EndoS from Group A Streptococcus (GAS), which very specifically removes the glycans on IgG antibodies. GAS only infects humans and causes mild infections like strep throat and swine pox, but also serious life-threatening infections. The role of bacterial endoglycosidases in the infection process is currently unknown. In this project, we want to try to answer this question. We have access to a very sensitive and accurate mass spectrometric method where we can study the glycosylation of antibodies directly in samples from blood, throat and infected tissue. Preliminary experiments show that antibodies lose their glycan both locally in tonsillitis and in the blood in severe disseminated infection (sepsis). We will also examine antibody glycosylation in mice infected with the original bacterium and those lacking EndoS or similar enzymes. The results from our studies are important for understanding the basic mechanisms of how bacteria evade our immune system, but also open up new ways to diagnose and treat severe infectious disease.
Erhardt, Sophie	Karolinska Institute	Novel Immune activation-based Drug Discovery Strategies for psychiatric disorders	Medicine	2016	Amount granted: SEK 3 000 000 Our project aims to identify biomarkers for psychiatric symptoms such as psychosis and suicidal thoughts. The aim is to refine clinical diagnostics and to promote personalized care. The research is hypothesis-driven and focuses on a low-grade inflammatory condition, and includes biochemical analyses on material from a large number of cohorts with different psychiatric disorders. Based on genetic and biochemical variations, we develop and validate animal models for detailed investigation of brain immune activation, neurotransmission and behavior. The project will combine extensive genetic and phenotypic information from patients with animal and cellular studies in a translational manner. A short-term goal is to find biomarkers to personalize drug treatment and identify patients at risk of suicide. A long-term strategic goal is to provide the Swedish pharmaceutical industry with information on new targets that directly relate to the mechanisms that cause the disease and improve productivity and quality of life for individuals with this lifelong disease. Based on our finding that patients with psychotic symptoms have elevated levels of kynurenic acid, several pharmaceutical companies have developed drug candidates that reduce the synthesis of kynurenic acid. We now have clear data showing that it is important to block another enzyme and are now also seeking funding to initiate a drug discovery project.
Eriksson, Ulf	Karolinska Institute	Role of VEGF-B mediated lipotoxicity in diabetic complications	Medicine	2016	Amount granted: SEK 2 000 000 Type 2 diabetes is a major medical challenge with several hundred million patients worldwide. The disease is also increasing rapidly and by 2030 the number of patients worldwide will exceed 500 million. Type 2 diabetes and diabetes-related complications are thus a dominant health problem with a strong socio-economic impact. The cause of the disease is not fully understood, despite the considerable resources invested in research over a long period of time. The onset of type 2 diabetes is strongly linked to vascular complications, resulting in reduced quality of life and premature death for many diabetes patients. We have identified a new and unique way to reduce insulin resistance, the initial pathological event leading to type 2 diabetes and the metabolic syndrome, by affecting the transport of blood fats through the blood vessel wall and thus the ability of different tissues to accumulate fat. This is achieved by regulating signaling via a vascular growth factor called VEGF-B. The overall aim of the research program is to investigate the role that VEGF-B signaling plays in the blood vessels in the development of type 2 diabetes, and in the diabetes complications seen in large and small blood vessels. We will focus on molecular, cellular and organ-specific events controlled by VEGF-B signaling, and the consequences of pathological fat storage and its role in disease development.
Brorsson, Ann-Christin	Linköping University	Lysozyme: A new treatment strategy for Alzheimer's disease	Medicine	2016	Amount granted: 616 000 SEK My research team has recently discovered that the protein lysozyme may have a neuroprotective effect in Alzheimer's disease (AD). AD is characterized by the formation of protein aggregates (plaques) in the brain that are mostly composed of the peptide Abeta. In our studies, we identified elevated levels of lysozyme in cerebrospinal fluid from AD patients and that the protein is localized in plaques in AD brains. We also saw that lysozyme can prevent aggregation and formation of toxic Abeta forms. Lysozyme was also shown to have a neuroprotective effect and the ability to counteract the disease process in transgenic Drosophila flies that can develop AD. In this project, we will map the mechanisms by which lysozyme can protect neurons from toxic Abeta peptides and block the formation of toxic Abeta forms. This knowledge will be crucial to understand the role of lysozyme in AD and determine the potential for lysozyme to be a therapeutic target for the disease.
Landegren, Ulf	Uppsala University	Development of pair-binding drugs	Medicine	2016	Amount granted: SEK 2 000 000 Drug development is expensive and difficult. New approaches are needed to more effectively develop highly specific drugs against a wide range of proteins. In the context of our successful work to develop proximity ligation for protein diagnostics, we note that detection of proteins requires the use of pairs of antibodies to achieve the desired specificity. We now want to utilize our knowledge of proximity ligation, as well as our experience in using DNA-coupled drugs for detection purposes, to develop a new technique to select pairs of drug substances that bind together to target molecules. The aim is to greatly improve treatment effects and minimize side effects. Our work, conducted in collaboration with SciLifeLab and its drug development arm, will utilize commercial libraries of drug compounds, linked to unique DNA strands. We will use proximity ligation to find pairs of compounds that together bind drug targets. The expected increase in binding strength will allow utilization of lower amounts of drugs, and reduce the risk of interference from extraneous proteins. We will also adapt such coincidental binders for exploitation as drugs, and we will compare their pharmacological effects with more conventional drugs in model experiments.
Pekna, Marcela	University of Gothenburg	New treatment strategy for obstetric asphyxia and strokes	Medicine	2016	Amount granted: SEK 3 000 000 Cerebral ischemia, i.e. oxygen deprivation due to lack of blood circulation after a stroke or during childbirth (asphyxia), causes great suffering for patients and their families and high costs to society. Brain cells in the ischemic tissue die and their functions are lost. Depending on the area of the brain affected, this can lead to difficulty controlling voluntary movements, loss of sensation, language and swallowing difficulties, epilepsy and more. Birth asphyxia with acute brain damage is an important cause of cerebral palsy. There is currently no effective way to repair damaged brain tissue and current research focuses on reducing the damage and improving functional recovery by stimulating the brain's plasticity that underpins our ability to learn and adapt. The complement system is part of the innate immune system and is best known for protecting us from dangerous bacteria. However, the complement system also has other important functions, not least in the brain. We have discovered that the complement system can protect brain cells from ischemia and stimulate the regeneration of neurons after a stroke. Our results show that treatment with a specific complement peptide increases brain plasticity and improves functional recovery after experimental stroke and birth asphyxia. Our goal is to build on these findings to develop new effective treatments for newborn children and adults with ischemic brain damage.
Bergman, Peter	Karolinska Institute	New treatment against multi-resistant bacteria by activating natural immunity	Medicine	2016	Amount granted: SEK 1 600 000 The goal of the project is to use a cellular infection model to study the activation of effector mechanisms in the natural immunity, such as antimicrobial peptides (AMP), autophagy and free oxygen radicals, which can contribute to the killing of resistant bacteria. We are already working on compounds that increase AMP production and activate autophagy, such as vitamin D and phenylbutyrate (PBA). In clinical studies, we have shown that vitamin D can reduce the burden of infection in immunosuppressed patients and that the combination of vitamin D and PBA can improve outcomes in tuberculosis. Now we have identified several new AMP inducers (APDs) that are more potent than both vitamin D and PBA. We have shown that an APD activates human macrophages and enables these cells to kill Klebsiella bacteria. The effect relies on a combination of free oxygen radicals, AMP and autophagy, making it extremely difficult for bacteria to develop resistance to this massive and coordinated immune attack. Interestingly, this APD also works against multidrug-resistant Klebsiella bacteria and together with cefotaxime a potent and synergistic effect is seen. Cefotaxime alone has no effect at all against these multi-resistant bacteria, but together with this APD, which activates the cell's own immune system, the resistant bacteria also die. "Now we want to go further and investigate the mechanisms in detail, include more bacteria, start animal studies and plan for clinical trials.
Ceccatelli, Sandra	Karolinska Institute	A novel approach to choose the best individual antidepressant treatment	Medicine	2016	Amount granted: SEK 2 000 000 Major depressive disorder (MDD) is a major cause of disability and affects the working age population worldwide. The prevalence is estimated to be around 10% in the general population (5% in Japan and 16% in the US). This serious disease has a major negative impact on both the individual and society. It takes several weeks, up to months, for the usual antidepressant medications to take effect, and symptom relief is achieved in only 30-40% of MDD patients. Thus, there is a strong need to improve the diagnosis and treatment of patients with depression. This project aims to develop a cost-effective and minimally invasive method to predict the response to antidepressant medication. The assay can be used in a clinical setting and represents a new diagnostic method for MDD patients with the aim of selecting the group that is sensitive to a particular antidepressant. This would prevent patients from taking a drug with no therapeutic effect for several months. The method we have developed is based on: 1. analysis of the patient's activity recorded with a bracelet; 2. analysis of genes (clock genes) in the patient's skin cells. The results will help doctors confirm the diagnosis and choose the right antidepressant treatment. Thus, shortening the duration of treatment and suffering, and giving new hope to patients with depression. In the longer term, it is possible that our method could also be applied to patients with other psychiatric conditions.
Smith, Ulf	University of Gothenburg	Type 2 diabetes - new markers and mechanisms	Medicine	2016	Amount granted: SEK 2 100 000 The application (two years) is focused on our new findings with a clear clinical translational connection. Within the period, we expect to initiate a clinical study with anti-Gremlin treatment of obese Type 2 diabetics (T2D) in collaboration with the pharmaceutical industry. All development work has been conducted at our laboratory, including with grants from the Foundation in 2014, and we have published a first work (Diabetes 2015) - however, outside the planned IPR application. Gremlin inhibits the effects of insulin in several tissues, is highly expressed and released by adipose tissue leading to high blood levels in obesity/T2D. It is also highly expressed in human macrophages and involved in M1/M2 phenotype regulation and inflammation. We will develop new animal models and identify sequences/signaling/receptors that inhibit insulin effects and drive inflammation. We have identified blood mannose as a novel and powerful marker for the risk of developing T2D and cardiovascular disease (Cell Metab 2016). It is unknown whether mannose is just a novel biomarker or of pathogenetic importance but our studies suggest the latter. We are planning to clarify this and initiate a clinical study with mannose administration. We have found that the microvascular endothelial cells regulate the ability of adipose tissue to normally take up and store lipids via the release of endogenous PPAR-activating lipids and that GPR 40 and ATGL play a crucial role in this. We will identify the lipids, synthesize them and clarify their clinical relevance.
Benson, Mikael	Linköping University	Multicellular disease models to find and functionally validate new drug targets in immune diseases	Medicine	2016	Amount granted: SEK 2 000 000 Treatment of inflammatory diseases is complicated by the fact that many different molecules and cell types are involved, and that these may differ at different times. Ideally, treatment would target an early molecule in an early cell type. This would require a multi-cellular disease model, showing in turn how all molecules in all cell types interact throughout the disease process. We recently described disease models in a single cell type, T cells, showing early and late disease processes in two inflammatory diseases, allergy and multiple sclerosis (Science Transl Medicine 2014 and 2015, Cell Reports 2016). The models were based on studying the activity of all human genes in T cells. We identified several molecules that could be suitable for targeted therapy. One of these was validated in an animal model of allergy, as well as by in vitro treatment of cells from allergic patients with a specific antibody. We now want to go further by constructing multicellular models of allergy and multiple sclerosis. The models are like puzzles where the pieces (=cells) are connected by linking molecules known to interact with each other. This will be done at different times to find out which cells start the diseases. We will search for 'starter molecules' and experimentally study whether these can be used for targeted treatment. If successful, the strategy may be transferable to find new medicines for all inflammatory diseases.
Hansson, Göran K.	Kungl. Academy of Sciences	Torsten Söderberg Academy Chair in Medicine 2017	Medicine	2016	Amount awarded: SEK 10 300 000 The Torsten Söderberg Foundation is currently funding five academic professorships in medicine at the level of SEK 2 million per year for five years. There is a great need for this type of research position, where proven outstanding professors are given the opportunity to further strengthen and develop their research. It is an important part of further strengthening Swedish research in the light of international developments. The professorship will promote internationally leading research in the medical field by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed based on the documented scientific quality of the research carried out. Particular emphasis is placed on research carried out during the last five-year period. The quality of the research program, the degree of innovation and the importance for the development of medical research will also be assessed.
Andersson, Ulf	Karolinska Institute	Development of new therapy for systemic inflammatory diseases using HMGB1 antagonists	Medicine	2016	Amount granted: SEK 1 500 000 An alarmin is a preformed molecule with a specific given intracellular cellular function but which can be released extracellularly as an inflammatory distress signal when cellular homeostasis is threatened. Our project studies whether therapeutic extracellular neutralization of the prototypical alarmin HMGB1, a common nuclear protein in all cells of the animal and plant kingdom, offers a possibility to improve the outcome of severe inflammatory systemic diseases, which are currently without effective therapy. We were instrumental in identifying HMGB1 as a key alarmin in 1999 and have since dedicated our research to HMGB1 biology. We have recently, for the first time ever, developed a neutralizing human anti-HMGB1 monoclonal antibody with impressive therapeutic efficacy in several different disease models mediated by HMGB1-TLR4 signaling. A typical example of such a disease is systemic inflammatory response syndrome (SIRS) caused by severe trauma or sepsis. This antibody will be brought to clinical trials with the financial support of a US academic institution. HMGB1 may also mediate tissue damage via interaction with RAGE receptors, where a better understanding of the mechanisms of action is required, which we aim to explore. We intend to select an HMGB1-specific Affibody® molecule to block RAGE binding.Typical diseases with this molecular background are systemic lupus erythematosus and several important neurodegenerative diseases.
Zierath, Juleen	Karolinska Institute	Epigenomic control and molecular characterization of insulin resistance in diabetes	Medicine	2015	Amount granted: SEK 1 600 000 Type 2 diabetes is caused by a strong resistance of the body's tissues to the hormone insulin and a reduced production of insulin by the pancreas. Both hereditary and lifestyle factors can cause insulin resistance but these factors are not yet understood. We will identify genes and proteins that contribute to the development of insulin resistance in human skeletal muscle, the largest tissue in the body, as well as mechanisms for how the genes may be affected by lifestyle factors such as exercise. By examining two different processes for how the environment and lifestyle factors/exercise can affect the genes, we can find genes that affect insulin resistance in the cells. The processes we will focus on are epigenetic changes such as DNA methylation and microRNA. By looking at all the DNA methylations that occur in insulin resistance, we can find genes that are affected. In addition, mapping all microRNA changes in insulin resistance provides additional genes that may be important for the development of type 2 diabetes. Finally, we will validate the identified genes above by examining their function on insulin sensitivity in mouse models of Type 2 diabetes. Information on which genes are affected will enable future development of new drugs as well as new dietary and exercise programs to treat and prevent the onset of Type 2 diabetes.
Syvänen, Stina	Uppsala University	Improved PET diagnostics for Alzheimer's disease	Medicine	2015	Amount granted: 427 850 SEK About 100,000 people in Sweden are currently living with Alzheimer's disease. The number of sufferers will increase as a consequence of increased life expectancy. The aim of the project is to develop positron emission tomography (PET, medical imaging technique) of soluble forms of the protein amyloid-beta (Abeta). Current PET technology, which is based on imaging the disease's characteristic senile plaques consisting of insoluble accumulations of Abeta, is not satisfactory because the signal "hits the ceiling" early in the disease. A PET scan therefore provides no information on the severity of the disease and cannot be used to measure drug effects. The antibody we have previously developed, mAb158, binds selectively to Abeta protofibrils, but like all other antibodies it is a large molecule that has difficulty passing from the blood into the brain. Over the past year, we have modified mAb158 so that, in addition to protofibrils, it also binds to the transferrin receptor, increasing the transport of mAb158 into the brain. Depending on how the modification is made, we have increased the uptake of the antibody 10-50 times. Furthermore, we have shown with PET that it is possible to image protofibrils in the brain in models of Alzheimer's disease. We will now study how sensitive the ligand is to changes in protofibril levels and further develop it for use in humans. The project is the first ever to successfully use an antibody as a PET ligand for a target system in the brain.
Pernow, John	Karolinska Institute	Molecular mechanisms and novel treatments for cardiovascular complications in diabetes	Medicine	2015	Amount granted: SEK 1 000 000 Diabetes is one of the main risk factors for the development of cardiovascular disease. A central reason for this is the malfunctioning of the endothelial cells of the blood vessels, leading to vasoconstriction and inflammation. Recent evidence suggests that the enzyme arginase is essential for the regulation of endothelial function by modulating the production of nitric oxide and free oxygen radicals. In addition, our research has shown that arginase in red blood cells may play an important role in cardiovascular function during oxygen deprivation. Our hypothesis is that increased activity of arginase in the blood vessel wall and red blood cells in diabetes results in reduced formation of nitric oxide, increased radical formation and vascular damage. The goal is to identify the regulation of arginase and to improve cardiovascular function in diabetes through arginase inhibition. These questions will be addressed first in experimental disease models and then in clinical studies. In experimental studies, the role of arginase in blood vessels and red blood cells in the development of cardiovascular dysfunction under oxygen deprivation will be investigated. In patients with diabetes and vascular complications, the regulation and activity of arginase in blood vessels and red blood cells is being investigated. The effect of arginase blockade on vascular function is being studied in controlled clinical trials. The project may lead to new knowledge about disease mechanisms and new treatment options to improve cardiovascular function and prevent complications in diabetes.
Ohlsson, Claes	University of Gothenburg, Sahlgrenska Academy	A new mechanism for regulating body weight	Medicine	2015	Amount granted: SEK 2 000 000 Obesity is a growing public health problem worldwide, with more than one billion overweight and 300 million obese according to the WHO. Obesity contributes to serious diseases such as diabetes and cardiovascular disease. In recent years, a number of reports have shown that people who spend much of their day sitting are at increased risk of obesity and diabetes. The reasons for this association are unknown. We have now obtained results suggesting that increased sitting may lead to less activation of a "body weight sensor" in the weight-bearing long bones and that this in turn leads to reduced activity in an anti-obesity system. There is already a well-known system that aims to keep body fat mass constant. The anti-obesity hormone leptin is released into the bloodstream from adipose tissue in proportion to the size of the fat mass. Leptin exerts a negative feedback loop in the brain leading to reduced appetite and obesity. Unfortunately, for unknown reasons, most obese people are insensitive to leptin's anti-obesity effect. Our clear preliminary data show that inserting weights into the abdominal cavity of mice reduces their food intake, body weight and fat mass in relation to the size of the weight and that this effect involves a specific cell type in the long tubular bones. We now want to study the exact mechanism of how the "body weight meter" affects fat mass and the possible clinical significance of this novel system of fat regulation.
Mallard, Carina	University of Gothenburg, Sahlgrenska Academy	The role of the immune system in neonatal brain injury: Molecular mechanisms and new targets for treatment	Medicine	2015	Amount granted: SEK 2 000 000 Being born prematurely increases the risk of brain damage, cerebral palsy and impaired cognitive and social functions. Prematurity is one of the major global health issues facing modern society according to the WHO (2012). These complications have a direct impact on the child's quality of life and are a huge burden socially and economically. Currently, there are no brain-protecting treatments. There is strong evidence of an association between inflammation, preterm birth and subsequent neurological diseases, which is the starting point for the current project. The main hypothesis is that inflammation in the blood leads to regulation of immune receptors (known as TLRs) at the blood-cerebrospinal fluid interface, contributing to inflammation and damage in the brain. By manipulating the immune response, we will be able to protect the immature brain. We will investigate: (i) the role of TLR2 in brain injury. (ii) the brain protective effect of newly discovered peptides in a clinically relevant animal model. (iii) the effect of brain-protective peptides on the inflammatory response in premature infants at increased risk of brain injury. Thus, we will be able to identify new mechanisms for how blood immune cells affect the immature brain, find new brain-protective treatments, gain important new knowledge about the regulation of inflammation in premature infants. This innovative project is thus likely to contribute new knowledge to develop treatments for premature babies.
Maeurer, Markus	Karolinska Institute	Personalized specific cell therapy for patients with glioblastoma and pancreatic cancer	Medicine	2015	Amount granted: SEK 2 000 000 Many studies show that T cells infiltrating tumor tissue have the ability to specifically recognize tumor cells. Treatment of cancer patients, using the patient's own T-cells isolated from tumor tissue, has been shown to result in a more than 70% durable response rate and we intend to offer a similar option to patients with cancer. The immune cells are grown in a controlled and sterile environment and activated to become more effective against cancer cells. Complete tumor by tumor analysis is performed with the intention of identifying the patient's mutation which acts as anti-tumor targeting TAAs (tumor associated antigens). The second layer of the approach uses transgenic T-cells that exploit the transmission of T-cell receptors (targeting so-called general tumor antigens, which are only found in tumors, not yet in healthy tissue) or use specific antibodies that target cancer (e.g. targeting mesothelin or FGVRvIII, "CARs") fused with molecules that enable T-cells to kill cancer cells. The aim is to identify the best tailored treatment and the best strategy to equip the patient's immune cells for the destruction of tumor cells: "personalized therapy" using a detailed evaluation of the patient's tumor and the patient's immune cells to offer the best approach to immunological treatment.
Karpman, Diana	Lund University	Studies on pathogenetic mechanisms leading to new treatment options in kidney diseases	Medicine	2015	Amount granted: SEK 2 000 000 The overall objective of this project is to study molecular mechanisms and develop new therapeutic options for certain kidney diseases. Starting from different kidney diseases, basic mechanisms leading to kidney failure will be studied. The project focuses on specific infections and immunological conditions that affect blood cells and kidney cells leading to inflammation and blood clot formation. Activation of the body's different protein systems on cells is studied to define which bacterial and host factors lead to disease. In addition, how certain gene alterations contribute to disease is studied. The kidney diseases studied are caused by infection, inflammation and/or immunological reactions. - We study small membrane particles released from blood cells and their role in spreading infection and inflammation, and how blocking these membrane particles can affect the course and development of kidney disease. - We have found a new mechanism of injury in kidney tissue and blocked it in patients with an attenuating effect on kidney inflammation. - We define new molecular mechanisms and gene mutations in kidney disease and study how these trigger kidney injury. By defining which factors contribute to disease development at the cellular level, in animal models and in patients, these studies can lead to the development of specific treatments, which are currently lacking. These new treatments focus on blocking the spread of infection and activation of inflammation.
Hesslow, Germund	Lund University	Associative learning and timing in the cerebellum	Medicine	2015	Amount granted: SEK 3 000 000 Memories are based on learned associations. The photo of a boat evokes the name of the boat, perhaps the smell of the sea. The sight of sheet music combined with a previous note causes the pianist to associate with the correct key. For this to be learned, the brain cells must establish new connections. It also requires a 'timing' mechanism to ensure that the key is pressed at the right moment How does this work? We can follow the learning of an association in a single neuron in the cerebellum. A test animal hears a tone followed by an air puff to the eye. After repeated such stimulations, the tone will trigger a blink before the puff of air - a conditioned reflex. The conditioned reflex is precisely timed - it comes just when the puff of air is expected with a precision of a few tens of milliseconds. We believe that the mechanism behind the timing is the same that allows the pianist to press the key at exactly the right moment. We have identified the cells in the cerebellum that learn the association and have discovered that these cells contain a kind of 'micro-clock'. We can pinpoint key components of the clocks' structure and want to go further to investigate the details. The discovery on which the project is based implies an entirely new principle for signaling and learning in the brain. The project may also have medical implications such as improved motor learning in stroke patients. As the same mechanisms appear to be damaged in children with autism and language disorders, the project may lead to better treatment for these as well.
Hansson, Göran K.	Kungl. Academy of Sciences	Torsten Söderberg Academy Chair in Medicine 2016	Medicine	2015	Amount granted: SEK 10 296 000 The professorship will promote internationally leading research in the medical field by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed based on the documented scientific quality of the research carried out. Particular emphasis is placed on research carried out during the last five-year period. The quality of the research program, the degree of innovation and the importance for the development of medical research will also be assessed. There is a great need for this type of research position, where proven outstanding professors are given the opportunity to further strengthen and develop their research, in order to further strengthen Swedish research in the light of international developments.
Ehrsson, Henrik	Karolinska Institute	How do we experience the body as our own? Research on cortex mechanisms	Medicine	2015	Amount granted: SEK 4 000 000 Bend your head forward and look down at your body. You see two arms, two legs, a stomach and a chest. But how does the brain understand that this body is your own? In our research project, we will use the most advanced brain imaging and brain stimulation techniques to answer this question. Our hypothesis is that the whole-body experience is created by two parallel cortex mechanisms. Signals from vision, touch and muscle sense are integrated in specific areas of the frontal lobe and the association cortex of the cerebral lobe to create the experience of a single coherent body, while processes in the temporal lobe generate signals about the location of this body in space. We will then go on to demonstrate that this brain's internal representation of the body affects episodic memory - one of our most important higher cognitive functions. Our hypothesis is that episodic memory requires us to have a functioning perception of our own body, and that this directly affects memory storage and recall. In summary, our results will provide a groundbreaking description of the cortex mechanisms that underlie whole-body spatial perception, and also demonstrate that this perception affects our episodic memory. These results could lead to important new advances in applied research on virtual reality, cognitive psychiatry and advanced prosthetics.
Dumanski, Jan	Uppsala University	Does Y chromosome loss in men cause cancer and Alzheimer's disease?	Medicine	2015	Amount granted: SEK 2 000 000 Women and men have different sets of sex chromosomes; women have two Xs and men have one X and one Y. It is also known that men have a shorter life expectancy compared to women, but the underlying mechanisms behind these differences are not understood. We have recently discovered that a lifelong loss of chromosome Y (abbreviated as LOY) in normal blood cells in adult or aging men is associated with: a) shorter survival and a significant risk of developing cancer in many different organs of the body; b) greatly increased risk of Alzheimer's disease; and c) smoking is strongly associated with LOY, which may explain why smoking is a major risk factor for cancer and Alzheimer's disease in men and, by extension, why men live shorter lives on average than women. We want to develop the possibilities of using LOY as a biomarker to assess the risk of cancer or Alzheimer's disease. We expect to prove that LOY in men has a strong effect on the risk of developing cancer and Alzheimer's disease, which could eventually lead to offering a LOY screening program for all adult men. We envision that within 5-15 years, all adult men will benefit from LOY status analysis. Since men on average live shorter lives and have a higher risk of developing cancer, we expect that our results will lead to lower mortality rates in the future among men who are included in LOY testing programs.
Bäckhed, Fredrik	University of Gothenburg, Sahlgrenska Academy	Metagenome platform and its role in metabolic diseases	Medicine	2014	Amount granted: SEK 2 000 000 Our gut contains 10 times more bacteria than we have cells in our body. These bacteria express 150 times more genes than we have in our human genome and influence several cellular processes in the gut such as blood vessel formation, immune system development and even our metabolism. We have previously shown that germ-free mice do not develop obesity and that the composition of the bacterial flora is different in obese mice and humans. This makes the gut microbiota a potential target for the development of new drugs and therapies for metabolic diseases. "Next generation sequencing has become a powerful tool for mapping the composition of the gut microbiota. However, the large data sets offer a major analytical challenge and even if we map the composition of the gut microbiota, animal studies are needed to understand how the gut microbiota affects our metabolism and metabolic diseases. The "Metagenome and its role in metabolic diseases" platform will bring together microbiology and systems biology in a unique translational setting and, in addition to studying whether the gut microbiome offers diagnostic or therapeutic targets for these diseases, will also study the underlying mechanisms using germ-free mice. As our platform will develop new analytical methods to study the composition of the gut microbiota, it will also constitute an important national resource for analyzing the composition and function of the gut microbiota.
Mona - Selsmark, Ann Christin		Muscle stimulation for the elderly and people with disabilities	Medicine	2014	Amount granted: SEK 220 000 For about 20 years I have been working with a microcurrent that strengthens muscles through isometric training without the client doing any work. This means a relief on joints and ligaments while strengthening the muscles. I have mainly worked with skiers, all disciplines, and private individuals. For the skiers, it was mainly injuries due to falls, skidding, oblique loads or overtraining and training pain. All could be helped with microcurrent and infrared heat. For these well-trained people, 1-5 treatment sessions may be sufficient. Other examples: 1. Disability due to a gunshot wound in the back with severely impaired mobility, atrophied muscles in both legs and pain as a result. Immediate pain relief, successively increased blood circulation and the warmth in the ice-cold lower legs returned after about 10 treatments. Microcurrent and infrared heat were used. The treatments have continued for several years. 2: Stroke with partial facial paralysis and weakness in the muscles and difficulty controlling the arm and leg on one side. Already after 5 treatments, the client could perform the "tweezer" grip, hold a book and perform some household chores. The client continues with the treatments and experiences clear improvement. 3. feet with severe pain, atrophied muscles, difficulty walking without special shoes. Already after the first treatment a severe pain in a big toe disappeared. Gradually the muscle strength has increased and the feet have increased in size and stability due to larger and stronger muscles. Now walks effortlessly. The treatments continue.
Westerlund, Fredrik	Chalmers University of Technology	Culture-free identification of antibiotic resistance	Medicine	2014	Amount granted: SEK 1 000 000 Bacteria becoming resistant to antibiotics is one of the major threats to global health. The WHO reported in April 2014 that we are approaching a 'post-antibiotic era', where common infections could become fatal unless we take dramatic action. New methods for diagnosing antibiotic resistance are therefore of great interest, partly to be able to implement the right medical treatment more quickly, but also to understand how resistance develops and limit its spread. In this project, I want to use a method I developed to identify the DNA that causes resistance within an hour after sampling instead of several days, as is currently the case. The key to speeding up identification so much is that the method we developed studies individual DNA molecules, eliminating the cultivation step, which is unavoidable in traditional techniques. The method is also compatible with equipment already available in all major hospitals and no major investment is required.
Pekna, Marcela	University of Gothenburg, Sahlgrenska Academy	Towards new treatment strategies for childbirth asphyxia and stroke	Medicine	2014	Amount granted: SEK 1 000 000 Brain ischemia, i.e. oxygen deprivation due to lack of blood circulation after a stroke or during childbirth (asphyxia), causes great suffering for patients and their families as well as high costs to society. Brain cells in the ischemic tissue die and their functions are lost. Depending on which area of the brain is affected, this can lead to difficulty in controlling voluntary movements, loss of sensation, language and swallowing difficulties, epilepsy, etc. Obstetric asphyxia with acute brain damage in newborn babies is a major cause of cerebral palsy. There is currently no effective way to repair damaged brain tissue and current research focuses on reducing the damage and improving functional recovery by stimulating the brain's plasticity that underpins our ability to learn and adapt. The complement system is a central part of the innate immune system and is best known for protecting us from dangerous bacteria. However, it also has other important functions, not least in the brain. We have shown that the complement system can protect brain cells against ischemia and stimulate brain plasticity. Our goal is to build on these findings to develop new effective treatments for newborn babies and adults with ischemic brain damage.
Sackey, Peter	Karolinska Institute	HMGB1, inflammation and cognitive function after severe sepsis	Medicine	2014	Amount granted: SEK 1 000 000 Every year, 40 000 patients are treated in Swedish intensive care units (ICUs). Over 35% of all ICU patients suffer from sepsis, with high mortality rates and multiple organ involvement. However, most survive. This group of patients suffers from various problems that make it difficult to return to their pre-infection life. Many patients describe affected cognitive function after sepsis but the association between sepsis and later cognitive problems is not well studied. The group's partners have found in animal studies that the level of a bodily inflammatory substance, High Mobility Group Box 1 (HMGB1), is elevated for months after sepsis and associated with cognitive problems. Cognitive function was restored with administration of HMGB1 monoclonal antibodies. HMGB1 administration to healthy mice caused cognitive dysfunction. The association has not been studied in humans. The project includes prospective cohort studies of ICU patients with/without sepsis, in order to follow HMGB1 levels and cognitive function one year after discharge from the ICU. The main questions in the project are whether there is a connection between severe sepsis, delirium and later cognitive dysfunction and whether cognitive dysfunction is linked to prolonged inflammation with elevated levels of HMGB1. If prolonged inflammation with HMGB1 elevation late in the course is linked to late cognitive problems after sepsis in humans, the findings may lead to future clinical trials of immunomodulatory therapy.
Gillberg, Christopher	University of Gothenburg, Sahlgrenska Academy	Autism in girls and women - brain function and symptoms	Medicine	2014	Amount granted: SEK 3 000 000 Autism and other early-onset developmental abnormalities (such as ADHD) (now often grouped together under the heading ESSENCE for Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) are thought to be much more common in boys than in girls. However, it has recently become apparent that many girls are being missed or misdiagnosed (often as depression, anxiety, eating disorder or personality disorder) in early childhood and that the 'correct' diagnosis is not made until adolescence or adulthood, while an increasing number of boys are being diagnosed at pre-school age. This means that girls do not have access to appropriate help and understanding with a high risk of psychiatric morbidity and social maladjustment from adolescence onwards. In this unique project, clinical picture and brain function will be examined in detail in young girls and boys and adult women and men with autism and other ESSENCE problems. The aim is to identify early symptoms and biological markers for autism and other ESSENCE so that girls can also receive correct early diagnosis and treatment/support from preschool age. The very latest technology in clinical child and adolescent psychiatry, psychometrics, brain imaging and neurophysiology will be used. The children/adults with autism and other ESSENCE included in the project come from the Gillberg Center's unique population-based cohorts of people with child neuropsychiatric disabilities.
Kokaia, Hall	Lund University	Developing new cell therapies for stroke	Medicine	2014	Amount granted: SEK 2 000 000 Every year, 30 000 people suffer a stroke in Sweden. Stroke is the most common cause of chronic disability among adults; two out of three stroke survivors have permanent motor, sensory or cognitive symptoms. Effective treatment to regain function is lacking. In this project, we use established animal models, in which transient blockage of blood flow in the middle cerebral artery results in structural and functional deficits similar to those in humans, to develop novel treatments for stroke. To replace the dead neurons in the cerebral cortex, we are reprogramming support cells in the damaged area into neurons or transplanting specific neurons, produced by reprogramming the stroke patient's own skin cells, into the stroke-affected brain. We are also adding immune cells (monocytes) to stimulate neuronal regeneration from the adult brain's own stem cells and from the transplanted cells, and to optimize other regenerative mechanisms. Within the framework of the project, we are also planning, based on positive animal experimental data, a phase 1/2 clinical study in stroke patients with the aim of improving functional recovery by adding monocytes in the post-ischemic phase. This translational research uses cell therapeutic strategies to recover brain function after stroke. If successful, the project could have a major impact on the treatment of many stroke patients.
Carlsson, Per-Ola	Uppsala University	Mesenchymal stem cells to stop type 1 diabetes development	Medicine	2014	Amount granted: SEK 2 000 000 Type 1 diabetes is the most common chronic disease in children for which there is no cure. At the onset of type 1 diabetes, there is a gradual cell death of the insulin-producing cells due to an immune attack, causing patients to lose all insulin production and become dependent on insulin injections. Insulin treatment is far from being able to mimic normal insulin production and individuals are at risk of developing a number of late complications of their disease such as blindness, kidney failure, heart attack, stroke and premature death. Previous studies have shown that specific cells in bone marrow, mesenchymal stem cells, can have powerful immunomodulatory properties, including preventing organ rejection after transplantation. These cells have also been shown in animal models of type 1 diabetes to prevent the onset of the disease. This research project aims to investigate whether the remaining insulin-producing cells can be rescued by transplantation with autologous mesenchymal stem cells in new-onset patients with type 1 diabetes, who have 20-40% remaining insulin production. In a Phase I/IIa study, we have seen maintained or increased insulin production in treated patients and no side effects. Through the use of autologous cells, no immunosuppressive drugs are needed. The successful development of a curative treatment for type 1 diabetes would be expected to have a major impact on society and especially the individual.
Pejler, Gunnar	Swedish University of Agricultural Sciences	The role of the mast cell in cancer	Medicine	2014	Amount granted: SEK 1 500 000 The mast cell is best known for its harmful effects in allergy, but much research suggests that the mast cell also has an important and harmful role in cancer. However, very little is known about the exact mechanism of action of the mast cell. When the mast cell is activated, it releases a number of components that are normally stored inside the cell's so-called secretory granules, such as various protein-degrading enzymes (proteases) and growth factors. Together, these components could have major effects on a tumor, such as facilitating the tumor's blood supply, but there is only limited knowledge about this. We want to find out exactly how the mast cell affects cancer. To this end, we will compare tumor development and metastasis in normal mice and mice that either completely lack mast cells, or lack different mast cell components. We will also investigate the role of mast cells in blood vessel formation, and isolate and characterize tumor mast cells from lung cancer patients. Furthermore, we will develop a novel technique to induce mast cells to commit "suicide" and investigate whether this technique can be applied to mast cells in clinical tumors. Since there is now much research suggesting that the mast cell has a detrimental role in cancer, there is a strong case for developing new cancer therapies and diagnostics that target the mast cell, e.g. to be used in combination with existing therapies/diagnostics. We believe that this project can contribute to such developments.
Smith, Ulf	University of Gothenburg, Sahlgrenska Academy	Prevention of the metabolic syndrome and ectopic fat	Medicine	2014	Amount granted: SEK 1 000 000 The project is focused on the obesity-related complications; Type 2 Diabetes (T2D) and Metabolic Syndrome (MS). Individual changes in the adipose tissue are linked to MS; in particular the ability to store fat in the subcutaneous adipose tissue and thus prevent fat accumulation in ectopic fat depots (liver etc.) and T2D/MS. We found that genetic predisposition to T2D (first-degree relatives, FDR) is linked to an impaired ability to store excess fat in the subcutaneous tissue, which is instead stored in ectopic depots. FDR has an impaired ability to recruit mesenchymal stem cells to adipogenesis in the subcutaneous tissue. The recruitment is dependent on BMP4 and FDR has increased levels of the BMP antagonist Gremlin1. BMP4 also regulates the ability to form oxidative beige/brown fat cells (anti-obesity) in the subcutaneous tissue, which is also inhibited by Gremlin1. Animal models, where we have increased BMP4 levels in the blood of mature mice (gene therapy model), have shown that they are protected from developing obesity and its complications due to increased beige/brown oxidative subcutaneous fat tissue. These findings will be developed into a possible new treatment for T2D/MS. We have also identified that a new family of lipids formed in the subcutaneous adipose tissue is released into the blood and is closely linked to insulin resistance. Administration of these lipids in animal models increases insulin action and improves glucose levels. We will further characterize their effects and plan to test them in humans.
Nilsson, Caroline	Karolinska Institute	Can we cure peanut allergy with oral immunotherapy and anti-IgE antibodies?	Medicine	2014	Amount granted: SEK 1 000 000 Severe food allergy (MA) is more common than severe asthma. Many people with SEA have a great fear of accidentally ingesting what they cannot tolerate and it is an invisible disability. Life-threatening allergic reactions, anaphylaxis, are mainly caused by soil/tree nuts but there is no cure. Oral immunotherapy (OIT), where the food is eaten in increasing amounts until a maintenance dose is reached, has been tried. Allergic reactions to OIT are a problem. Anti-allergy antibody (anti-IgE) is a drug that binds allergy antibodies and prevents the allergic reaction. Stimulation of basophilic cells with allergen in test tubes (CD-sens) reflects the individual's allergen sensitivity. Three pilot patients have undergone treatment with anti-IgE and OIT, followed by CD-sens, with good results. Question: Can we improve quality of life and can tolerance be developed in adolescents with severe AD? Method: The study is independent of pharmaceutical companies. 20 adolescents with severe peanut allergy are treated with anti-IgE and start OIT with peanut (escalation from 1-10 g/day) during continued anti-IgE treatment, when CD-sens to peanut is 0. Anti-IgE treatment is tapered when the participant has eaten 10 g peanut/day for 2 months. Benefit: A curative treatment without severe side effects for those with severe AD would be of great benefit. The individual with MA can avoid the fear of life-threatening allergic reactions and unplanned hospital visits with possible hospitalization. There are major health economic benefits to be gained.
Normark, Staffan	Kungl. Academy of Sciences	Torsten Söderberg Academy Chair in Medicine 2015	Medicine	2014	Amount awarded: SEK 10 000 000 The professorship will promote internationally leading research in the medical field by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed based on the documented scientific quality of the research carried out. Particular emphasis is placed on research carried out during the last five-year period. The quality of the research program, the degree of innovation and the importance for the development of medical research will also be assessed. The professorship is worth SEK 10 million over five years.
Collin, Mattias	Lund University	Translational glycoimmunology - from pathogens to drugs	Medicine	2014	Amount granted: SEK 2 000 000 About half of all our proteins are decorated with carbohydrate structures. These give proteins essential properties such as solubility, half-life, protection against degradation, and are often part of the functional interaction surfaces with other proteins. Proteins in the immune system are no exception; for example, antibodies are completely dependent on carbohydrates to function. Bacteria that live in more or less harmony with us have learned to influence these carbohydrates in different ways during evolution. We have shown that endoglucosidases from pathogenic bacteria can modify carbohydrates on human antibodies with dramatic effects on their immune-stimulating functions. These effects can be exploited to switch off a faulty immune response in several animal models of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, autoimmune anemia and autoimmune bleeding disease. Some of our enzymes have also been used as tools for the production and analysis of antibody-based drugs. However, we have only scratched the surface of the probably very extensive arsenal of carbohydrate-modifying enzymes found in our normal flora and pathogenic bacteria. Increasing our knowledge of the structure and function of such enzymes increases our understanding of how bacteria interact with us in health and disease. In addition, new types of enzymes can be of great importance for the modification and analysis of new protein drugs.
Aperia, Anita	Karolinska Institute	Why Chronic Kidney Disease is a Risk Factor for Cardiovascular Disease	Medicine	2014	Amount granted: SEK 1 000 000 Chronic kidney disease is common but often underdiagnosed. About 10% of the population is estimated to have some form of kidney damage. Cardiovascular disease is much more common in people with kidney damage than in the general population and is the most common cause of death in kidney failure. Although the link between chronic kidney disease and cardiovascular disease has been known for over 100 years, the cause is not yet known. We have found in preliminary studies that the hormone Angiopoietin2, which if it reaches the circulation leads to pathological changes in blood vessels, is highly present in kidney tissue from rats with chronic kidney disease. Our hypothesis is that, in kidney disease, large amounts of this hormone are formed and released, leading to pathological changes in the blood vessels. We test our hypothesis in 3 steps. 1) We study the molecular mechanisms behind increased Angiopoietin2 production in kidney cells that are exposed to the stress of dealing with the increased amount of egg white secreted in the diseased kidney. 2) In rats with human kidney disease, we study the function, structure and amount of Angiopoietin2 in the kidney and vessels. 3) We study a group of young patients with chronic kidney disease with respect to the amount of Angiopoietin2 in blood and stiffness in arteries. If we succeed in identifying the molecular mechanism behind the link between chronic kidney disease and cardiovascular disease, this will enable the development of a targeted treatment to protect against the cardiovascular complications.
Tegnér, Jesper	Karolinska Institute	TGF-β, RAPA and IL23 Dependent Regulatory Circuits in Human TH17 Cells and Induced Tregulatory Cells	Medicine	2012	Amount granted: SEK 1 500 000 Patient-oriented research has clearly shown that the risk of getting another disease increases when the patient already has a disease. This has been demonstrated not least by Swedish registry research. Since the sequencing of the human genome in 2000, a very large number of genetic studies have been carried out and today we know that over 1000 different genetic DNA variants in the genome can be associated with various common diseases. An interesting finding in these studies is that several diseases share genetic variants, which suggests that different diseases may have similar biological mechanisms where especially immune-related genes recur. In the last 5-10 years, there has been an explosive development in translational cellular immunology where the adaptive immune system controls the development of diseases such as MS, RA, CVD, psoriasis, various cancers and gastrointestinal diseases. Several phase III studies are therefore underway where drugs that attack specific cellular mechanisms of these so-called TH17 and Treg cells in the adaptive immune system. There are also drugs on the market today that affect these cells' production of various inflammation-inducing cytokinins. In our project, we intend to experimentally map key signaling pathways in humans in these two cell types using new powerful genomic techniques closely linked to bioinformatic analysis. The clinical relevance is that we will be able to identify new selective mechanisms that intervene in the inflammation and also find new biomarkers.
Zierath, Juleen	Karolinska Institute	How genes and environment affect insulin sensitivity in skeletal muscle in diabetes	Medicine	2012	Amount granted: SEK 1 500 000 Type 2 diabetes is caused by a strong resistance of the body's tissues to the hormone insulin and a reduced production of insulin by the pancreas. Both hereditary and lifestyle factors can cause insulin resistance but these factors are not yet understood. We will identify genes and proteins that contribute to the development of insulin resistance in human skeletal muscle, the largest tissue in the body, as well as mechanisms for how the genes may be affected by lifestyle factors. By unbiasedly investigating two different processes for how the environment can affect the genes, we can find genes that contribute to insulin resistance in the cells through the influence of lifestyle factors. The two processes we will focus on are so-called epigenetic changes of DNA (DNA methylation) and microRNA. By looking at all the DNA methylations that occur in insulin resistance, we can find the genes that are affected. In addition, we will scan all microRNA (miRNA) changes in insulin resistance to understand the role of these genes in the development of type 2 diabetes. Finally, we will validate the new genes identified above by investigating their function on insulin sensitivity in mouse models of Type 2 diabetes. Information on which genes are affected will enable future development of new drugs as well as new dietary and exercise programs to treat and prevent the onset of Type 2 diabetes.
Svensson, Torgny	Karolinska Institute	Developing more effective drugs for schizophrenia, bipolar disorder and major depression	Medicine	2012	Amount granted: SEK 1 000 000 The project aims to develop new and improved medicines for schizophrenia, bipolar disorder and major depression, estimated by the EU as some of the most costly diseases for both society and patients, which is of key importance for psychiatry as current medicines are far from optimal and have a number of undesirable side effects. The research is based on extremely urgent clinical problems and aims to identify, using advanced basic science methodology and selective pharmacological tools, new targets for drugs that can be used in psychosis and bipolar disorder as well as in major depression. This includes some new antipsychotic drugs, such as asenapine, but also so-called allosteric AMPA receptor potentiators and glycine uptake inhibitors, as well as direct and indirect nicotinic alpha7 receptor agonists, which have recently been shown to have therapeutic effects in schizophrenic patients. Our research can stimulate drug development in the field that is currently losing momentum, not least in Sweden. The results have been met with great interest both among psychiatrists and the international pharmaceutical industry.
Söderberg Nauclér, Cecilia	Karolinska Institute	Studies on a new cytomegalovirus (CMV) for tumorigenesis, new treatment strategies in sight?	Medicine	2012	Amount granted: SEK 2 000 000 New evidence suggests that a virus, cytomeglaovirus (CMV), can be detected in several different tumors such as brain tumors, neuroblastoma, breast, colon and prostate cancer. We also find the virus in metastases from these tumors, but not in healthy tissue surrounding the tumor cells, suggesting that CMV plays an important role in the development of these tumors. Recently, we discovered that it is not the usual form of CMV that is found in tumors, but instead a new CMV variant that is detected in 90-100% of said tumors. We believe that the new CMV variant can play a significant role in tumor development, and that therapies targeting this virus in the future will hopefully be able to be used to improve existing cancer treatment as it may be able to target the root cause of the tumor. Our experience today shows that brain tumors treated with anti-CMV drugs have a significantly improved survival two years after diagnosis, indicating that this strategy may be possible in the future. In this project we will characterize the new CMV strain, identify new biomarkers for the virus for clinical diagnostics and we intend to develop new treatment strategies for CMV positive cancers.
Svensson, Mikael	Karolinska Institute	Repair of damaged spinal cord with peripheral nerve grafts and transplantation of stem/progenitor cells	Medicine	2012	Amount granted: SEK 2 500 000 The aim of this project is to link basic research to clinical applications that benefit patients with neurological injuries. Our group is well positioned to study human stem cells from adult patients' brains through the organization and lab resources we have built up over the last 10 years. How can we use this knowledge of our nervous system and, more importantly, transfer it to our patients? We have chosen to focus on spinal cord injury where the need for scientific success is high. In a recent article published in Cell Transplantation, we have shown that stem cells can be transplanted into the nervous system with some success where these immature cells form new neurons and synaptic connections. In addition to stem cell transplantation, we have revisited the idea of repairing an injured spinal cord by bridging the area of injury with peripheral nerve grafts. We have shown that nerve fibers can be made to grow past (regenerate) the damaged area through these grafts. Using neurophysiology (motor evoked potentials), we have shown that after 3 months the regeneration establishes contact between the cortex and lower limb muscles. These studies have now led to a clinical trial where patients with spinal cord injury will be operated on using this technique starting in 2013.
Nordquist-Brandt, Elisabeth	Sahlgrenska University Hospital	Investigation of new clinical potential of the monoamine stabilizing substance OSU6162	Medicine	2012	Amount granted: SEK 2 000 000 OSU6162 is a drug developed by Professor Arvid Carlsson. The pharmacological action has been characterized as dopamine- and serotonin-stabilizing with beneficial effects in neuropsychiatric diseases. OSU6162 has also been shown to be almost free of side effects. In relatively recent treatment trials, it was somewhat surprisingly observed that the preparation had a significant and positive clinical effect on mental fatigue. In a double-blind cross-over study in 12 patients with mental fatigue triggered by stroke or traumatic brain injury, a significant effect was seen, which in some patients was quite dramatic. Extended open clinical trials to study the safety and long-term efficacy of OSU6162 are now planned. The optimal dosage of the drug and the side effect profile of the drug will also be further studied. These studies may include patients with different diagnoses, as previously studied in placebo-controlled trials with OSU6162. There are theoretical reasons for assuming that OSU6162 can counteract various symptoms of narcolepsy and thus replace the currently dominant but problematic central stimulants. Twelve patients with narcolepsy are planned to be included in a randomized double-blind cross-over comparison with placebo. Efficacy will be evaluated using rating scales and self-reporting of symptoms.
Normark, Staffan	Kungl. Academy of Sciences	Funds for the creation of an additional Academy Chair in Medicine	Medicine	2012	Amount granted: SEK 10 163 000 The Torsten Söderberg Foundation and the Ragnar Söderberg Foundation are currently funding five research professorships in medicine and the Torsten Söderberg Foundation is itself funding an academic professorship (currently being filled) in medicine at the level of SEK 2 million per year for five years. There is a great need for this type of research position, where proven outstanding professors are given the opportunity to further strengthen and develop their research, in order to further strengthen Swedish research in the light of international developments. The professorship will promote internationally leading research in the medical field by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed based on the documented scientific quality of the research carried out. Particular emphasis is placed on research carried out during the last five-year period. The quality of the research program, the degree of innovation and the importance for the development of medical research will also be assessed. This grant will allow an additional five-year academic chair to be filled in 2013.
Steensland, Pia	Karolinska Institute	Evaluation of the dopamine stabilizer OSU6162 as a new medicine for the treatment of alcohol dependence.	Medicine	2012	Amount granted: SEK 986 000 Alcohol addiction is classified as a disease - but effective treatment is lacking. The need for new drugs is great. We have the necessary expertise to bridge the gap between basic research and clinical practice and thus accelerate drug development. One challenge in treating alcohol dependence is to prevent relapse, which is driven by a strong craving for alcohol that persists even after long-term sobriety. The ability to resist these cravings is also limited, as alcohol-dependent people have impaired impulse control. Dopamine increases when you drink alcohol - you feel intoxicated. However, with repeated intoxication, dopamine levels decrease, creating discomfort - a strong craving for alcohol - which can drive alcohol-dependent individuals to start drinking again. Dopamine is also involved in impaired impulse control. The dopamine system is therefore a possible target for new drugs for alcohol dependence. Dopamine stabilizers are a new group of drugs (developed by Nobel Prize winner Arvid Carlsson) that can normalize dopamine levels in the brain. This is sought after in the effective treatment of alcohol dependence. Our results show that the dopamine stabilizer OSU6162 reduces alcohol intake and relapse drinking in rats. We will now study how OSU6162 affects the release of dopamine in the brain and whether OSU6162 itself is addictive. We will also study for the first time whether OSU6162 can reduce alcohol cravings and improve impulse control in alcohol-dependent humans.
Li, Jia-Yi	Lund University	Assessment of far-reaching spread of Parkinson's pathology in Parkinson's disease	Medicine	2012	Amount granted: SEK 3 000 000 Recently, we have shown that transplanted fetal dopamine-producing neurons develop Lewy body pathology more than 10 years after surgery in patients with Parkinson's disease (PD), suggesting the spread of disease from the host environment to the transplanted cells. Evidence also shows that the progression of Lewy body pathology occurs in anatomically interconnected nerves and that these susceptible neurons are not neurotransmitter-dependent, suggesting long-distance transport of the diseased protein, alpha-synuclein (a-syn) and its aggregates, Lewy bodies and Lewy neuron protrusions. However, these hypotheses have not yet been tested. Our hypothesis is that a-syn oligomers and fibrils are central to the long-distance spread of Lewy body pathology. Using both in vitro and in vivo models, in combination with imaging techniques to study living cells and biochemical processes, we will address two key questions about how PS can spread: (i) Whether, and if so how, oligomeric and fibrillar a-syn are transported via antero- and/or retrograde transport within the neuron, and (ii) Whether, and how, these a-syn species can be transported between neurons. Successful demonstration of the patterns and underlying mechanisms of long-range spread of Lewy body pathology in nerves will open new avenues to identify novel targets to intervene in PS pathogenesis and slow, or stop, the progression of the disease.
Liljeqvist, Jan-Åke	Sahlgrenska Academy	Development of a vaccine against herpes simplex virus type 2 infection	Medicine	2012	Amount granted: SEK 3 000 000 There is an urgent need for a vaccine against herpes simplex virus type 2 (HSV-2) infection. Firstly because HSV-2 is the most common sexually transmitted infection with >500 million infected individuals globally, and secondly because HSV-2 infection greatly increases the risk of HIV transmission. We have shown that HSV-2 glycoprotein G (gG-2) is necessary for HSV-2 to spread to the nervous system after genital infection and that gG-2 together with adjuvant provides good protection as a vaccine in a mouse model. The aim of the project is to present a new vaccine concept against HSV-2 infection based on gG-2. We will now optimize the process for large-scale production of gG-2 with a view to toxicological studies prior to phase I studies in humans. Prophylactic and therapeutic effects will be studied in an additional animal model, different adjuvants will be evaluated and immunological mechanisms will be mapped to understand why gG-2 provides protection during vaccination. The project has good prospects for successful continuation with support from several stakeholders such as the Swedish Research Council, VINNOVA, Innovationsbron, Novo Nordic A/S and GöteborgBIO.
Lundberg, Jon	Karolinska Institute	The importance of diet and oral flora for the cardiovascular system and metabolism	Medicine	2012	Amount granted: SEK 4 000 000 Nitric oxide (NO) is a neurotransmitter produced in the body by specific enzymes which, among other things, contributes to a healthy cardiovascular system and regulates metabolism. Reduced production of NO is a contributing factor to the development of atherosclerosis, high blood pressure and age-related diabetes. We have discovered an alternative mode of NO formation where the inorganic ion nitrate (NO3-) is reduced to NO. Nitrate is formed naturally in the body as a residual NO product but is also abundant in our diet, mainly in green leafy vegetables. Oral bacteria play an unexpected key role in NO formation by reducing nitrate accumulated in saliva to the more reactive nitrite ion (NO2-). Nitrite is then absorbed into the body where numerous enzymes can reduce it further to NO. The project aims to study the role of oral bacteria and our diet in the formation of NO and how this affects the body in health and disease. Researchers' view of our oral bacteria has been permeated by a negative image over the years. These bacteria are thought to be responsible for everything from trivial problems such as bad breath and tooth decay to more serious diseases such as tooth loss and cancer. We hope to show that parts of the oral flora are instead of great benefit and can help form an important neurotransmitter. In this way, the naturally high nitrate content of vegetables may contribute to the well-known beneficial effects of these foods on the cardiovascular system.
Johansson, Jan	Karolinska Institute	Mechanisms of BRICHOS protein aggregation prevention and treatment potential in Alzheimer's disease	Medicine	2012	Amount granted: SEK 2 500 000 Alzheimer's disease is the most common form of dementia, which causes impaired memory, attention and language comprehension due to the loss of nerve cells. One of the reasons why nerve cells shrink is that a small protein, called beta-amyloid or Abeta, changes and begins to clump together into plaques of amyloid. There seems to be something in the process where Abeta goes from a healthy protein to amyloid plaques that are toxic to nerve cells. "We study a protein part called BRICHOS, which has been found in many different proteins, including the brain. BRICHOS has been shown to effectively prevent Abeta from clumping together to form amyloid. This makes administration of BRICHOS or activation of the body's own BRICHOS completely new possible treatment strategies for Alzheimer's disease. We will now further study how BRICHOS affects Abeta and how it can prevent Abeta from becoming toxic to neurons. So far, we have used experiments in test tubes, cultured cells and fruit flies. Fruit flies are used as a model to study whether BRICHOS can prevent Abeta from becoming toxic in a living brain, and our preliminary results are very promising. BRICHOS prevents aggregation of Abeta and counteracts impaired neuronal function. Therefore, we now want to further study how to administer BRICHOS to the brain, and how well BRICHOS prevents Abeta aggregation and toxicity in mouse models of Alzheimer's disease.
Jonsson, Ann-Beth	Stockholm University	Bacteria-host interplay during disease progression	Medicine	2012	Amount awarded: SEK 2 250 000 Infectious diseases kill millions of people every year. This project maps how bacteria that cause meningitis, sepsis and cancer interact with host cells. By understanding critical steps in the disease process, we aim to develop new ways to treat, cure and prevent these diseases. The growing prevalence of antibiotic resistance makes it increasingly urgent and pressing to find new medicines for bacterial infections. The bacterium Helicobacter can cause gastritis, ulcers and eventually cancer. We have found a substance that specifically attacks the disease-causing functions of the bacterium. We want to develop this compound to go into clinical trials and test this as a new treatment method and a future alternative to antibiotics. Other serious bacterial diseases include blood poisoning and meningitis, which are dreaded medical emergencies. Still, mortality rates are as high as 15-50% according to various studies, which is due to the fact that the infection caused general activation of the inflammatory and coagulation systems. By mapping the infection, we have found new receptors and signaling pathways used by the bacteria. At the same time, the immune system needs to be characterized, as mortality is often due to the bacteria overstimulating our immune system. An important part of the project is to find new ways to influence these systems so that the disease process can be stopped.
Kettunen, Petronella	Sahlgrenska Academy	Mechanisms of amyloid-induced memory impairment and neurodegeneration	Medicine	2012	Amount granted: SEK 1 750 000 We have developed the first functional zebrafish model of memory loss in Alzheimer's disease (AD). These "demented" fish have lost their ability to learn a simple escape behavior after injection of amyloid β, Aβ, into the brain. In Aβ-treated animals, there is also increased neuronal death and inhibition of caspases and p53 indicates that the learning problems are caused by cell death. We have also observed colocalization of fluorescent Aβ in dead neurons and microglia in vivo. Furthermore, we have injected fish with brain extracts from Alzheimer's patients and patients without dementia. Animals injected with AD brain cannot learn, while those injected with healthy brain have normal learning. This is the first time it has been shown that memory problems can be induced by brain extracts from AD patients. We are now further investigating how Aβ leads to neurodegeneration. We follow the formation of plaques, how neurons are killed and how microglia interact with the plaques. Important genes for disease progression are knocked out and learning ability/cell survival is measured. An interesting finding is that the learning ability in Aβ-injected animals returns after a few days, as previously observed in rodents. We believe that the mechanisms, such as clearance or regeneration, could form the basis for future patient treatment. We will also use the new model to screen future drugs and rapidly test genetic and clinical findings from patient material.
Eriksson, Kristina	Sahlgrenska Academy	How does the natural immune system work in the placenta and newborn during a viral infection?	Medicine	2012	Amount granted: SEK 1 500 000 Newborn babies are highly susceptible to infection because their immune systems do not function as well as those of older children and adults. Children infected at or shortly after birth have much more serious infections, resulting in one million newborns dying each year from infection. The hypothesis is that the newborn's immune system is adapted to survive the fetal period, and that a more well-functioning immune system in the fetus would lead to spontaneous abortion. The aim of the project is to investigate why newborn babies have such a severe disease course when infected with the herpes virus, and whether this is linked to fetal survival in the womb. We are investigating how white blood cells from newborn babies work and how they react when they come into contact with the virus, and comparing this with how cells from adults react. We will also study whether white blood cells can be involved in preterm birth, i.e. premature babies. We do this in the placenta, the part of the uterus that protects the baby from infections and from being attacked by the mother's immune cells. We hope that these studies will enable us to prevent/treat preterm birth and severe herpes virus infections in newborns.
Hansson, Gunnar C.	Sahlgrenska Academy	Defects in the inner mucus layer of the colon in ulcerative colitis	Medicine	2012	Amount granted: SEK 2 000 000 Our hypothesis, contrary to the prevailing models, is that the disease ulcerative colitis is due to defects in the inner mucosal layer of the colon that allow bacteria to penetrate it and trigger an inflammatory reaction when the bacteria reach the epithelial cells. We will now go on to examine the molecules and the changes they undergo in the large intestine so that the mucus first forms a dense mucus layer, sticks, then loosens and expands in volume and becomes a home for all the bacteria in the gut. Most of these events take place around the MUC2 mucin, which will be altered by cutting it in different places. Besides MUC2, there are many other proteins that we think or know are important for the proper functioning of the inner mucus layer. There are probably many different reasons why this inner mucus layer can fail, ranging from genetic defects in the MUC2 mucin to particularly aggressive bacteria that form, just as we have shown for a parasite, enzymes that can cause the inner mucus layer to break down. We will now collect material from a large number of patients with ulcerative colitis. In this material we will look for mutations in MUC2 and other interesting proteins, measure mucus thickness and especially mucus permeability. We will look at the composition of the mucus both by analyzing which genes are expressed and which proteins are present (proteomics) and study which bacteria are present and which proteins they produce.
Eriksson, Lars Ingvar	Karolinska Institute	Respiration and cognition after anesthesia and surgery	Medicine	2012	Amount granted: SEK 1 500 000 The project describes the mechanisms behind serious complications in respiratory and brain functions after anesthesia, and how we will create new treatment methods and safer care after surgery/trauma in adults and children in the future. We study the most common causes of serious incidents and long-term effects after anesthesia, surgery and intensive care, namely disturbances in respiratory regulation in case of oxygen deficiency and consciousness and cognitive ability. Serious adverse events after anesthesia/surgery due to disturbances in respiration, consciousness or cognitive functions can be explained by interactions with vital signaling pathways in respiratory control and the nervous system. With unique analyses of human oxygen-sensitive cells, we can describe central and peripheral regulation of respiration and how this regulation is affected by anesthesia and surgery. In animal and cell models, we further map the body's natural response to surgery/trauma and how we can use specific neurotransmitters to prevent postoperative cognitive disorders and dementia. We have built up advanced cellular and molecular biological research methodologies as well as physiological measurements in humans, anesthetized animals and individual cells to map in detail the effects of anesthetics on key functions behind the regulation of breathing, consciousness and cognition. This project increases knowledge of these regulatory systems and how they are affected by anesthesia and intensive care and has already created new routines for postoperative care both nationally and internationally.
Flower, Anna	Lund University	Strategies developed by pathogenic bacteria to outsmart the human complement system	Medicine	2012	Amount granted: SEK 4 000 000 Infectious diseases are a global problem and about a third of total deaths are related to infections. Despite the successful development of antimicrobials in the 20th century, there has been a dramatic increase in antibiotic resistance in recent years. In order to develop new prophylactic methods and treatment strategies, it is essential to understand how pathogenic bacteria can manipulate the immune system.Any successful pathogen must avoid and defend itself against the complement system, a key component of the innate immune system, and develop mechanisms that allow the microbe to survive, colonize and, in the worst case, invade the host. The overall goals of the project are to increase the knowledge of the underlying mechanisms of microbial survival and find new therapeutic opportunities. We will highlight how bacteria can avoid attacks from the complement system by hijacking human or producing their own complement inhibitors and how they use complement receptors to attach to and invade epithelial cells. We will focus on respiratory pathogens such as streptococci. In addition, studies are planned to investigate the role of periodontal bacterial pathogens in the development of rheumatoid arthritis as such association is evident in epidemiologic studies.
Cao, Yihai	Karolinska Institute	Translational research of anti-angiogenesis in cancer therapy	Medicine	2012	Amount granted: SEK 4 000 000 Several common cancer drugs based on antiangiogenesis have become key components in the treatment of patients with different types of cancer. While antiangiogenic drugs in combination with chemotherapy significantly improve patient survival, the clinical benefits of antiangiogenic therapy alone remain modest. There are a number of still unresolved clinically related fundamental questions. Why does only combination therapy produce positive effects in patients? Why do patients become resistant to antiangiogenic therapy? How can we optimize existing treatments to maximize clinical benefits? Which biomarkers predict clinical benefit? In this research project, we seek to understand the basic mechanisms of antiangiogenic cancer therapy and translate our preclinical findings into clinical use to improve antiangiogenic cancer treatment. We will use different preclinical models to approach these clinically relevant questions. We also study the role of angiogenesis in cancer metastasis. In particular, we are interested in studying changes in vascular structures that facilitate tumor spread, invasion and metastasis. We will continue to study lymphangiogenesis, which is important as many tumors spread via the lymphatic system. Overall, our research program is translational in nature and the results generated by our research will benefit millions of cancer patients.
Berghard, Anna	Umeå University	Establishing a nerve and the olfactory nerve as a model for nerve-brain barrier healing	Medicine	2012	Amount granted: SEK 495 000 Our research has helped to show the connection between the development of the olfactory nerve and so-called GnRH cells (gonadotropin-releasing hormone cells). If the development of the olfactory nerve is disrupted, GnRH cells do not reach their final location near the pituitary gland. GnRH cells regulate sexual development and fertility, which cannot occur if this developmental stage shows a high degree of disruption. It is unusual combinations of genetic changes that underlie the disorders, which is in line with our working hypothesis that it is the interaction between many different types of cells that is involved in establishing a nerve. We address whether the so-called nerve-brain barrier cells participate in nerve establishment. The project is expected to show which precise step(s) in the formation of the olfactory nerve fails and thus causes lack of GnRH.By using the olfactory nerve as a model, new information is also expected on how nerve cell axons interact with a number of other, relatively little studied cell types to form and maintain the nerve-brain barrier. Nerves connect the periphery and the brain, making it important to know how the barrier allows axon passage but is not permeable to e.g. infectious agents, metastatic cells or toxic substances. Little is known about the cells of the barrier and how they are affected by nerve damage. The area around the olfactory nerve also contains an area for drainage of the fluid produced in the brain, making the healing process of the nerve-brain barrier in this area important to understand.
Alftberg, Åsa	Lund University	The ideal and practice of medication. An ethnological study of older people's use of medicines.	Medicine	2012	Amount granted: SEK 151 500 Older people today use many medicines. Their use has increased significantly over the last twenty years. This is partly because new medicines have been introduced and can now be used for treatment, but also because ageing has been medicalized as a condition that should be treated. But medicines do not only have biological effects, they also have social and cultural consequences that affect people's daily lives. The focus of this study is on how the individual uses the medicine, how the medication is administered and what meaning and significance the medication creates. What norms, cultural beliefs and practices does medication require to be taken into account? How is the individual's identity ultimately affected? The aim of the study is to provide knowledge about the complex relationship between the ideals and practice of medication, i.e. the relationship between the prescription, how the medicine is intended to be used, and how it is actually handled. The study is based on people aged 80 and over living in their usual homes.
Arner, Peter	Karolinska Institute	The turnover of fat cells and their fat content in humans. Mechanisms and clinical significance	Medicine	2012	Amount granted: SEK 1 000 000 Reduced resistance to the hormone insulin (insulin resistance) can cause the most common form of diabetes (type 2 diabetes) and other common conditions. We have long been investigating the role of adipose tissue in insulin resistance in humans. We have shown that the turnover of fat cells (formation and death) and their fat content (uptake and release) are important and that this is regulated by inflammation in the adipose tissue. Part of the project addresses the mechanisms behind these findings. It is also known that the adipose tissue forms a large number of different adipokines that are released into the circulation. We believe that several of these >600 adipokines may affect insulin sensitivity. The application also aims to define these candidates for insulin resistance and their regulation. The project may provide new treatments for type 2 diabetes and insulin resistance as well as being used for preventive treatment.
Rudin, Anna	Sahlgrenska Academy	The role of regulatory T cells and gut bacteria in reducing allergy risk	Medicine	2011	Amount granted: SEK 1 000 000 The allergic immune response is almost always established in childhood. Allergies result from an over-reaction to harmless proteins in allergens to which the immune system is not supposed to react and are due to a defective number or function of regulatory T-cells. These T cells can be stimulated by the normal flora in the gut and it is thought that an altered gut flora early in life is a cause of poorer regulation of the immune response to allergens. The project follows children from birth to six years of age to study the relationship between gut microbiota, regulatory T cells and allergic immune response and disease. This is a unique project as it is prospective and a collaboration between immunologists, bacteriologists and pediatric allergists. Preliminary data show an association between a type of bacterium in the gut early in life and increased numbers of regulatory T cells, and an association between increased numbers of regulatory T cells and allergic disease. The aim of the project is to find support for administering a killed bacterium or bacterial product on the intestinal mucosa early in life to prevent the development of allergic disease.
Wold, Agnes	Sahlgrenska Academy	New strategies to curb the allergy epidemic	Medicine	2011	Amount granted: SEK 2 000 000 Allergy is the most common chronic disease among children and young adults in Sweden today. Allergies are almost non-existent among the population in poor countries and among children who have grown up on farms with animal husbandry. In this project we investigate which lifestyle and environmental factors are associated with protection against allergy development. Our aim is to provide a science-based strategy to protect future children from developing allergy. In particular, we are focusing on three approaches: - Stimulation of the child's immune system through natural exposure to a complex oral flora - Intake of fats that dampen the immune system's propensity to induce allergic immune responses - Development of an allergy 'vaccine' based on bacterial 'superantigens' that stimulate the infant's immature immune system and support tolerance development. Our studies are based on carefully monitored birth cohorts where lifestyle factors, diet, gut flora and immune responses are registered and analyzed in relation to allergy development, as well as relevant animal models to study the active mechanisms. We believe that our approach can lead to the development of effective strategies to curb the allergy epidemic that plagues the Western world and also affects the population in countries where economic development is accelerating and living conditions are improving.
Marklund, Stefan	Umeå University	Neurotoxicity of superoxide dismutase-1 and other causes of amyotrophic lateral sclerosis (ALS)	Medicine	2011	Amount granted: SEK 4 500 000 In amyotrophic lateral sclerosis (ALS), the motor nerve cells that control the body's muscles die. The most common cause is inherited mutations in the protein superoxide dismutase-1 (SOD1), which is found in 6% of cases. We have recently presented evidence that normal SOD1 is also involved in the majority of ALS cases that lack mutations. The project aims to investigate this link further to understand the factors that trigger the disease. The studies are based, among other things, on transgenic mice that develop ALS during production of human SOD1 in the spinal cord. Complementary studies are focused on ALS patients without SOD1 mutations, and on patients with the related disease frontal lobe dementia. A second goal is to clarify how SOD1 causes ALS at the molecular level. Aggregation of SOD1 in neurons is central to the disease. We see that SOD1 aggregates are of two different types, depending on the mutation, and that ALS pathology differs between these aggregates. This link between aggregate type and pathology is found in the infectious prion diseases. We will now investigate whether the SOD1 aggregates can spread the disease via injection in the nervous system of transgenic mice with varying genetic backgrounds. Furthermore, we will map at the atomic level how the aggregates arise inside living human cells with newly developed strategies based on NMR. The goal is to identify suitable targets in SOD1 for targeted therapy with antibodies, which, by inhibiting aggregation, slow or prevent the spread of the disease in the nervous system.
Normark, Staffan	Kungl. Academy of Sciences	Torsten Söderberg Research Chair in Medicine	Medicine	2011	Amount awarded: SEK 10 000 000 There is a great need for this type of research position, where proven outstanding professors are given the opportunity to further strengthen and develop their research, in order to further strengthen Swedish research in the light of international developments. This research professorship will promote internationally leading research in the medical field by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed based on the documented scientific quality of the research carried out. Particular emphasis is placed on research carried out during the last five-year period. The quality of the research program, the degree of innovation and the importance for the development of medical research will also be assessed.
Poellinger, Lorenz	Karolinska Institute	Development of new therapeutic strategies for vascular regeneration in ischemic tissues	Medicine	2011	Amount granted: 650 000 SEK The research concerns a protein that detects low oxygen levels in a tissue. When oxygen levels are low, such as in the heart in the case of atherosclerosis, the function of this protein is activated, and it will activate genes that are important for the formation of new blood vessels (to increase oxygen supply) and for adapting the tissue's metabolism to the low oxygen levels. The latter is important for the exposed tissue's ability to survive the oxygen starvation. In this project, we want to use the protein that detects low oxygen levels to increase vascular regeneration in heart muscle or brain that is exposed to low oxygen levels due to reduced blood supply. In contrast to single growth factor therapies (which have a limited effect), this system represents a promising new approach to restore the oxygen balance in the diseased tissue. In detailed molecular studies, we will try to develop techniques to effectively activate the oxygen-sensitive protein, thus keeping an oxygen-starved heart cell (or brain cell in the case of stroke) alive. We will also investigate how different genes will be regulated when cardiovascular tissues are exposed to low levels of oxygen, e.g. in models of peripheral vascular disease, atherosclerosis and increased blood pressure in the pulmonary circulation. The project will provide important knowledge to increase vascular regeneration and exert positive effects on metabolism in tissues exposed to low oxygen levels (ischemia).
Larsson, Jonas	Lund University	Development of new methods for blood stem cell expansion - implications for cell therapy in hematological diseases	Medicine	2011	Amount granted: SEK 700 000 The aim of the research is to identify and characterize genes that regulate the growth of blood stem cells. It is the blood stem cells that are responsible for the regeneration of the blood system during bone marrow transplantation. This is a life-saving treatment for thousands of blood cancer patients every year. Unfortunately, a large number of patients are still unable to receive this treatment due to insufficient stem cells. It is therefore essential to find ways to make stem cells multiply before transplantation. A large number of research groups around the world have been working on this for a long time without much success and we currently know very little about the mechanisms that regulate the growth of blood stem cells. We have developed a genetic screening method based on so-called RNA interference (RNAi) that makes it possible to systematically inhibit the function of thousands of genes in hematopoietic stem cells and then study how this affects the growth of the stem cells. In our experiments with this method, we have succeeded in identifying several genes that can be inhibited to increase stem cell growth. In parallel with new screening experiments, we are now studying some of these genes in detail to understand how they affect stem cell function and whether they can be exploited to propagate blood stem cells outside the body under clinically relevant conditions.
Liljeqvist, Jan-Åke	University of Gothenburg	Development of a vaccine against herpes simplex virus type 2 infection	Medicine	2011	Amount granted: SEK 1 200 000 There is an urgent need for a vaccine against herpes simplex virus type 2 (HSV-2) infection. Firstly, because HSV-2 is the most common sexually transmitted infection with >500 million infected individuals globally, and secondly because HSV-2 infection greatly increases the risk of HIV transmission. We have shown that HSV-2 glycoprotein G (gG-2) is necessary for HSV-2 to spread to the nervous system after genital infection and that gG-2 together with adjuvant provides good protection as a vaccine in a mouse model. The project aims to present a new vaccine concept against HSV-2 infection based on gG-2. Now, prophylactic and therapeutic efficacy will be studied in an additional animal model and immunological mechanisms will be mapped to understand why gG-2 provides protection during vaccination. The project has good prospects for successful continuation with support from several stakeholders such as the Swedish Research Council, VINNOVA, Innovationsbron AB, Novo Nordic A/S and Göteborg BIO.
Kisessling, Rolf	Karolinska Institute	Immunotherapy of cancer with genetically modified T cells	Medicine	2011	Amount granted: 650 000 SEK Cancer immunotherapy with genetically modified T cells. With several breakthroughs in basic immunological research, we are on the verge of a new generation of cancer therapies. There is now potential to develop immunotherapy based on well-defined molecules expressed on cancer cells and on the immunologically active white blood cells. Recent results show that immunotherapy can have a clinical impact, prolonging life and activating the immune system in a proportion of patients with severe cancer. However, methods need to be improved as only a proportion of patients respond to these treatments. Therefore, the aim of the research is to transfer the knowledge of modern immunology into clinically useful treatments for cancer, in close collaboration between researchers at Cancer Center Karolinska, doctors at Radiumhemmet and other research groups in the EU. A current series of experiments is testing whether white blood cells, known as lymphocytes, can be altered by modern genetic methods and thus manipulated to fight the patient's cancer cells. The method has already shown promising but preliminary results in the treatment of malignant melanoma, and it will be investigated whether it also works in patients with other types of cancerous tumors. The studies are carried out in collaboration with several other European laboratories.
Karlsson, Mikael	Karolinska Institute	Regulation of B cells in inflammatory diseases	Medicine	2011	Amount granted: SEK 1 200 000 Our immune system protects us from infections and the inflammatory response resulting from its activation is designed to fight the infection and then restore the balance in the body. In autoimmune disease, this balance is disrupted and the inflammatory process goes out of control and instead participates in the destruction of different tissues depending on the disease. A key component of this misguided immune response is B cells, which usually produce antibodies against viruses and bacteria. The importance of these cells has been highlighted recently as a treatment that knocks them out (rituximab) has been effective in a number of rheumatic diseases. It has been known that the rheumatic disease SLE is linked to cardiovascular disease. In this project we investigate the mechanisms behind this link with a focus on the B-cell. The goal is to find new markers that can predict whether SLE patients will develop cardiovascular complications and to find methods to control B cells so that their beneficial properties are utilized in the treatment of inflammatory diseases.
Karpman, Diana	Lund University	Bacterial virulence factors, innate immunity and prothrombotic mechanisms in kidney disease	Medicine	2011	Amount granted: SEK 4 000 000 Chronic kidney disease often leads to kidney failure. We study four kidney diseases: Hemolytic Uremic Syndrome (HUS), Thrombotic Thrombocytopenic Purpura (TTP), vasculitis and IgA nephropathy. HUS is characterized by low platelets, anemia and acute renal failure. There are two variants. Typical HUS is caused by intestinal infection with enterohemorrhagic Escherichia coli (EHEC) bacteria. There was a very large outbreak in Europe in May-June 2011. Atypical HUS is associated with gene mutations in complement proteins, part of the innate defense system. This activates the complement system and attacks the body's own cells. TTP involves a mutation in ADAMTS13, a plasma enzyme that cleaves von Willebrand factor within the blood's delivery system. This leads to the formation of blood clots. TTP patients have the same symptoms as HUS including fever and neurological symptoms. Vasculitis is characterized by inflammation of blood vessels that affects the blood supply to several organs, especially the kidneys. The cause is unknown but the body's own white blood cells and the immune system play a crucial role. IgA nephropathy is the most common form of kidney inflammation in the Western world. It can be triggered by upper respiratory tract infections. Our studies aim to identify the molecular mechanisms behind these diseases, both bacterial and host factors. We aim to map how the body's cells are affected, how blood cells are activated and vessels are damaged, in order to develop specific treatments that are currently lacking.
Holmdahl, Rikard	Karolinska Institute	From genes and disease mechanisms to treatments for rheumatoid arthritis	Medicine	2011	Amount granted: SEK 2 000 000 Chronic inflammation appears to be a contributing factor in a number of major diseases, such as rheumatoid arthritis (RA). No preventive or curative treatment is yet available for RA or other chronic inflammatory diseases. We study experimental animal models with similar diseases to humans. These animal models allow us not only to identify the disease genes but also to study how they work. We will humanize the animal models so that we can directly study the genes identified in RA in an experimental model. Thus, we can also use these experimental animal models to investigate entirely new principles and new drugs to prevent and cure disease. We are concentrating on developing a) a new type of immune-specific vaccine against RA, b) a new type of diagnostic method where a large number of antibodies in serum can be simultaneously analyzed, c) a new type of treatment with oxidants developed on the basis of our genetic findings.
Cao, Yihai	Karolinska Institute	Cold-induced lipolysis and angiogenesis significantly contribute to development of cardiovascular disease	Medicine	2011	Amount granted: SEK 2 000 000 Coronary heart disease (CHD) caused by atherosclerosis is the most common cause of death in the western world, including Sweden and the rest of the Nordic countries. It has been reported that CHD incidence increases several times during the cold season and the highest incidence of CHD occurs in winter. Our aim is to understand the basic mechanisms of cold-induced lipolysis in CHD development that is related to atherosclerosis. Through this research, we hope to develop new approaches to the treatment and prevention of cardiovascular diseases. We plan to use animal models of different vascular diseases under different conditions to study the role of temperature changes on plaque development in atherosclerosis, including introducing/removing some specific genes in animal models. We will use drugs according to different principles, either alone or in combination to treat atherosclerosis-related heart disease, and collaborate with clinical cardiologists and experts to perform clinical studies. Although the activation of brown adipose tissue is generally positive against obesity and diabetes, there are no studies on the question of how cold induces fat dissolution in the development of atherosclerosis. If our preclinical findings can be successfully translated into clinical settings, millions of patients who find themselves at risk of cardiovascular disease could benefit from our work. Our project therefore has significance for the benefit of millions of patients.
Frostegård, Johan	Karolinska Institute	Impaired natural immunity to phospholipid antigen as a cause of chronic inflammatory disease, mainly cardiovascular disease and atherosclerosis: a new hypothesis	Medicine	2011	Amount granted: SEK 2 000 000 Atherosclerosis is a chronic inflammatory disease that leads to cardiovascular disease (CVD). Since the mid-1990s, our group has been interested in how a particular type of fat, phospholipids, when oxidized ("hardened") can cause the inflammation of atherosclerosis. We have put forward a new hypothesis for atherosclerosis and CVD: low levels of natural antibodies against these fats including phosphorylcholine (anti-PC) cause CVD independently of and in the same order of magnitude as the established risk factors. In experimental studies, we have shown that anti-PC counteracts precisely the type of inflammation that is central to atherosclerosis. We have also shown that other antibodies against lipids, such as oxidized cardiolipin and phosphatidylserine (aOxCL and aOxPS), have similar properties. The aim is to develop improved risk assessment and develop new treatments (vaccines and/or antibodies for atherosclerosis and CVD and potentially for other inflammatory diseases). We combine animal, cell and clinical studies. In animal studies, we vaccinate with the lipids and deliver the antibodies themselves. The cell experiments test how immune responses in atherosclerosis are affected and the clinical studies investigate the role of the new factors, in several unique cohorts. Atherosclerosis and its consequence cardiovascular disease are dominant health problems. A new type of immunologically relevant risk factors and treatment based on natural immunity, focusing on lipids such as PC, OxCL and OxPS, may have a major impact.
Hansson, Stefan	Lund University	New diagnosis and cure for pre-eclampsia (preeclampsia)	Medicine	2011	Amount granted: SEK 2 900 000 Preeclampsia is one of the most serious pregnancy-related diseases in the world, affecting 8.5 million women annually. There is currently no specific diagnosis or prediction method, nor a cure. We believe we can make early, reliable diagnosis by measuring fetal and adult hemoglobin and alpha-1 microglobulin (A1M) in the mother's blood. Our in vitro studies indicate that we should be able to cure the disease by giving A1M.
Arnberg, Niklas	Umeå University	Viral receptors: importance for tropism, therapy and targeting	Medicine	2011	Amount granted: SEK 1 000 000 Viruses cause a variety of more or less severe diseases in humans. In this project, we are mapping the molecules and mechanisms that regulate how viruses (winter flu viruses and so-called adeno- and picornaviruses) bind to and infect human cells. This determines, among other things, which cell types, tissues and organs viruses ultimately infect (virus "tropism"). We want to use newly acquired knowledge about these molecules and mechanisms to develop new drugs that prevent viruses from binding to and thus infecting cells. Our research results can also be used to improve so-called gene therapy, which means 'treatment with genes'. Harmless, 'disarmed' adenoviruses are excellent carriers of foreign genes and efficiently transport different genes into our cells. We and many others believe that in the future it will be possible to treat and/or prevent cancer, infections, hereditary diseases and metabolic disorders using gene therapy. This type of treatment is sensitive and needs to be fine-tuned in several ways. One such way is to ensure that the genes are delivered to the right cells. So disarmed viruses must be steered away from their usual target cells, and instead be directed to the very cells that need treatment. If we can learn more about the molecules and mechanisms that 'real' viruses use to bind to and attack human cells, it will be easier to direct disarmed, gene-carrying viruses to the right type of cells.
Brorsson, Ann-Christin	Linköping University of Technology	Interdisciplinary studies of the aggregation process of the amyloid beta peptide - parallel analysis of transgenic fruit flies and biophysical measurements	Medicine	2011	Amount granted: SEK 200 000 The research studies the aggregation process of the amyloid (A) beta peptide linked to Alzheimer's disease. Alzheimer's is a dementia disease in which the nerve cells in the brain break down. To combat the disease, it is important to: a) identify which structures of the A-beta peptide are toxic to neurons, b) determine how the toxic structures attack the cells, and c) find molecules that can prevent the formation of toxic A-beta structures. To achieve these goals, fruit flies that can form toxic A-beta structures in the central nervous system are used. In parallel, the aggregation process of the A-beta peptide is also studied in a simpler environment, in test tubes, with different biophysical measurement techniques such as spectroscopy and microscopy, as well as how toxic A-beta structures attack cells from both rats and humans. By combining these studies, it is possible to link the emergence of different structures of the A-beta peptide with their ability to cause neuronal degradation and thus identify the structures that are toxic to the cells. This information is important for finding new treatments for Alzheimer's disease. Banana flies are also used to test different molecules (drug candidates) that can protect cells from being degraded by toxic A-beta structures or counteract the formation of toxic A-beta structures, thus preventing the onset of the disease.
Bäckhed, Fredrik	Sahlgrenska Academy	Developing a platform to study the metagenome and its role in metabolic diseases	Medicine	2011	Amount granted: SEK 9 000 000 Our gut contains 10 times more bacteria than we have cells in our body. These bacteria express 150 times more genes than we have in our human genome and influence several cellular processes in the gut such as blood vessel formation, immune system development and even our metabolism. We have previously shown that germ-free mice do not develop obesity and that the composition of the bacterial flora is different in obese mice and humans. This makes the gut microbiota a potential target for the development of new drugs and therapies for metabolic diseases. "Next generation sequencing has become a powerful tool for mapping the composition of the gut microbiota. However, the large data sets offer a major analytical challenge and even if we map the composition of the gut microbiota, animal studies are needed to understand how the gut microbiota affects our metabolism and metabolic diseases. The "Metagenome and its role in metabolic diseases" platform will bring together microbiology and systems biology in a unique translational setting and, in addition to studying whether the gut microbiome offers diagnostic or therapeutic targets for these diseases, will also study the underlying mechanisms using germ-free mice. As our platform will develop new analytical methods to study the composition of the gut microbiota, it will also constitute an important national resource for analyzing the composition and function of the gut microbiota.
Svanborg, Catharina	Lund University	Genetics of innate immunity and host susceptibility to acute and chronic infection	Medicine	2010	Amount granted: SEK 4 500 000
Wallberg-Henriksson, Harriet	Karolinska Institute	Torsten and Ragnar Söderberg Foundations' anniversary donation (part 2)	Medicine	2010	Amount granted: SEK 25 000 000
Smith, Ulf	University of Gothenburg	Wnt activation - role in obesity and its complications	Medicine	2010	Amount granted: SEK 4 500 000
Hellstrand, Kristoffer	University of Gothenburg	New treatment strategies for cancer and viral infections	Medicine	2010	Amount granted: SEK 4 500 000
Normark, Staffan	Kungl. Academy of Sciences	Application for 10 million SEK for the creation of an additional research chair in medicine.	Medicine	2010	Amount granted: SEK 5 087 500
Bokarewa, Maria	University of Gothenburg	Proto-oncogenes as effectors and therapeutic targets in inflammation and autoimmune arthritis	Medicine	2010	Amount granted: SEK 4 500 000
Cao, Yihai	Karolinska Institute	Translational study on angiogenesis in regulation of obesity and diabetes	Medicine	2010	Amount granted: SEK 2 700 000
Enerbäck, Sven	University of Gothenburg	Functional brown adipose tissue in healthy humans- a new target for anti-obesity therapy	Medicine	2010	Amount granted: SEK 4 500 000
Swoboda, Peter	Karolinska Institute	Is schizophrenia a ciliopathy?	Medicine	2013	Amount granted: SEK 1 100 000 Schizophrenia is a complex, chronic illness that can affect up to 1% of the population. Symptoms include hallucinations, personality disorders, distorted perception of reality, etc. The symptoms of the disease are caused by errors in the interaction of nerve cells. Schizophrenia is caused by environmental factors and genetic changes. Our research suggests that a number of schizophrenic genes are controlled by a special class of control genes, which in turn are normally important for the function of the cell's antenna, known as cilia. Cilia are found on neurons, where they are important for receiving signals from the environment. Being able to discern a link between the function of the cell antenna and the onset of schizophrenia is of great interest. We can then directly clarify the molecular mechanisms behind the disease and how they (cilia) affect the function of neurons. We use human neurons that have such an antenna, a cilium. We change the function of the schizophrenic genes and cilia and observe the effect directly in the cells. To see how schizophrenic genes affect the interaction of neurons, we use a mask as a model where the nervous system and all the connections between cells are mapped. The same principles apply to the mask and the human nervous system. In the mask, we can genetically alter individual neurons, detecting changes in their connections and activity. Our results can be used in the future to test the impact of different drugs and therapies on neuronal function.
Tryggvason, Charles	Karolinska Institute	Laminins - cell differentiation, phenotype stability, pancreatic island expansion	Medicine	2013	Amount granted: SEK 1 000 000 Most cell types in the body are located on or directly attached to thin connective tissue structures (basement membranes) that contain specific laminin proteins, which come in over 16 different forms and are tissue-specific. The laminins are important for cell differentiation binding and for the tissue-specific stability of cells. We are the only research group that has produced these highly complex proteins and studied them. We have shown that laminins have several
Sverremark-Ekström, Eva	Stockholm University	Microbial exposure, immunological maturity and allergy development in children	Medicine	2013	Amount granted: SEK 1 000 000 The early years of life are central to the maturation and balance of our immune system. Many factors can influence this, including how and when we are exposed to different microorganisms. Changing exposure to different microbes is thought to be one reason for the recent marked increase in various inflammatory diseases. For example, allergies in children have increased significantly and are now a global health problem. Our research has previously shown a clear link between the presence of lactobacilli in the very early gut flora and early infection with two very common herpes viruses and a reduced risk of allergy development. We have also been able to show that these types of early microbial stimulation affect the immune system in a way that may partly explain the 'allergy-protective' effect. Here, we want to go further and study in detail the interactions between these microorganisms and the immune system at different ages and investigate how it relates to allergy development. The project will provide information on basic immunological processes during childhood and on how different types of microorganisms can affect children's immunological profile and allergy development. The studies are of an experimental nature but have a strong clinical basis. In our studies we use cell lines, animal models and experimental systems as well as material from a very well characterized allergy cohort, where we can correlate all findings to clinical parameters and allergy status up to 10 years of age.
Olofsson, Anders	Umeå University	Preeclampsia, Alzheimer's and Skelleftea disease - causes and links?	Medicine	2013	Amount granted: SEK 470 000 Amyloidosis is the result of a pathological phenomenon in which aggregating proteins are deposited in tissue. Today, 30 different diseases are associated with amyloidosis, including Alzheimer's and Parkinson's disease. Amyloid deposits of the plasma protein transthyretin (TTR) are directly linked to the development of familial amyloidosis with polyneuropathy (FAP), a progressive nerve disease also known in Sweden as Skelleftejukan. Preeclampsia is a serious complication that affects 5-8% of all pregnancies and is one of the most common causes of fetal death. The cause of pre-eclampsia has been unknown until now. However, we will soon publish results describing how aggregates of TTR are very likely to be the direct cause of the disease. This is a breakthrough in many ways where parallels between the different diseases can now be made. FAP is one of the few amyloidoses that is currently clinically treatable and a drug and the possibility of treating pre-eclampsia according to the same principle is a very interesting question. Interestingly, the results also suggest that transthyretin may have an additional function in the body that could be linked to the development of Alzheimer's disease. Taken together, these findings, in addition to increasing our basic understanding of these diseases, provide opportunities for the development of new treatments.
Schmidtchen, Artur	Lund University	Harnessing the body's immune system to fight infection and inflammation	Medicine	2013	Amount granted: SEK 1 000 000 Infection and inflammation are behind many diseases. We can suffer from conditions such as chronic skin eczema, or chronic wounds, diseases in which we often see an overactivation of our immune system, leading to harmful and uncontrolled inflammation. Wound infections in burns or post-surgery (which in the worst case can lead to sepsis) are other major problems in healthcare, where we currently lack effective prevention strategies and are forced to use a lot of antibiotics. Infection treatments today only attack the microbe, and not the activation of various inflammatory cascades in the body. It is therefore crucial to develop alternative strategies to counteract infections and the subsequent harmful inflammatory process in wounds and various skin diseases. We have recently discovered several innate protection systems in the body that operate in our skin and during wound healing, based on various antibacterial and immunosuppressive peptides. Based on these discoveries, we are trying to develop therapies based on the modulation of the body's own innate immunity. These "natural" and interfering strategies are more effective and sustainable with respect to the development of resistance, and we therefore hope that the research will expand our treatment options, and complement existing treatments in both local infections (wound infections, postoperative, eczema), as well as deep infections and sepsis.
Mjösberg, Jenny	Karolinska Institute	Innate lymphoid cells in inflammatory bowel disease	Medicine	2013	Amount granted: SEK 500 000 Chronic inflammatory bowel disease (IBD) carries a dramatically increased risk of colon cancer. It is likely that the chronic inflammation in IBD is a direct cause of colon cancer. I, along with several other research groups, have recently discovered a new family of cells in the immune system. These are called 'innate lymphoid cells' (ILCs) and are found in both mice and humans. In mice, these cells have a very important role in intestinal inflammation and tumor development, but the specific link between ILCs in IBD and colon cancer in humans has not yet been established. The aim of my project is to investigate the role of ILCs in IBD and colon cancer and find new therapeutic targets associated with ILCs that can be utilized for the prevention and treatment of these diseases. My hypothesis is that these cells are directly involved in the development of IBD and thus colon cancer and also have an active role in regulating cancer growth. Through access to unique gut tissue samples and advanced molecular biology techniques, I can directly study ILCs located in the inflamed or malignant tissue. I can determine their function in detail and thus determine the role these cells may play in IBD and colon cancer. My research will increase the understanding of this group of cells in general, and especially their role in IBD and colon cancer. IBD can be seen as a precursor to cancer. Thus, knowledge about IBD is extremely important to prevent the development of colon cancer.
Normark, Staffan	Kungl. Academy of Sciences	Creation of an additional academic chair in medicine	Medicine	2013	Amount granted: SEK 10 200 000 The Torsten Söderberg Foundation and the Ragnar Söderberg Foundation are currently funding five research professorships in medicine and the Torsten Söderberg Foundation itself is funding two academic professorships (one of which is being filled) in medicine at the level of SEK 2 million per year for five years. There is a great need for this type of research position where proven outstanding professors are given the opportunity to further strengthen and develop their research and is needed to further strengthen Swedish research in the light of international developments. The professorship will promote internationally leading research in the medical field by enabling the holder to devote full-time to research for five years at a Swedish medical faculty. The holder of the professorship will be appointed based on the documented scientific quality of the research carried out. Particular emphasis is placed on research carried out during the last five-year period. The quality of the research program, the degree of innovation and the importance for the development of medical research will also be assessed.
Ohlsson, Claes	Sahlgrenska Academy	Is WNT16 a key protein that reduces the risk of bone fractures?	Medicine	2013	Amount granted: SEK 2 000 000 Osteoporosis is one of our major public health problems. Bone fractures caused by osteoporosis lead to great suffering and significant costs for the patients affected.The inhabitants of Sweden and Norway have the highest risk of bone fractures in the world. The reason for this is unknown and it is therefore of great strategic importance to conduct osteoporosis research in Sweden. The overall objectives of the application are to develop more effective and safer treatment methods for patients with osteoporosis and to increase knowledge of the causes of osteoporosis. The studies include both experimental animal studies and clinical patient studies. I have recently identified a number of genetic risk markers and potential drug targets for bone fractures. We will evaluate whether the identified genetic regions that have been shown to increase the risk of osteoporosis are indeed important for bone fracture risk and if so, we will investigate in detail how they affect fracture risk. My human genetic studies and subsequent studies in transgenic mice have recently shown that the endogenous protein WNT16 reduces the risk of bone fracture by increasing the thickness of compact bone. We are now using advanced cell culture systems and transgenic mice to investigate in detail how WNT16 protects against bone fractures. Our working hypothesis is that WNT16 is released from the bone-forming osteoblasts and inhibits the bone-degrading osteoclasts.
Lindbom, Lennart	Karolinska Institute	New strategies to prevent vascular leak in acute inflammation	Medicine	2013	Amount granted: SEK 500 000 Sepsis is a dreaded complication of bacterial infections that, despite advanced intensive care, can lead to circulatory collapse and organ failure with high mortality rates. Increasing prevalence of antibiotic resistance contributes to difficulties in successfully treating these conditions. An essential component in the development of the disease is damage to the blood vessels of the lungs, resulting in leakage of blood plasma into the lung tissue. The lung injury is mainly due to the activation of white blood cells, particularly neutrophilic granulocytes. We have shown that proteins released from storage vesicles in the granulocytes (e.g. HBP/azurocidin) strongly contribute to the impairment of the blood vessel barrier function during inflammation. The research program aims to further elucidate mechanisms for the impact of white blood cells on blood vessel integrity in inflammatory disease states including sepsis. In particular, it will investigate new possibilities to therapeutically counteract the harmful activity of granule proteins in acute systemic inflammation. The program will hopefully establish a completely new approach to the treatment of complications in severe infectious conditions which may lead to the development of unique drugs in this field.
Mathé, Aleksander	Karolinska Institute	New treatment for severe recurrent depression: intranasal neuropeptide Y	Medicine	2013	Amount granted: SEK 1 400 000 Depression is a leading cause of disability and premature death, including co-morbidity with cardiovascular disease and suicide (>1,500/year), affecting approximately 1 in 4 women and 1 in 7 men in their lifetime. The European Commission/Brain Council report (2011) highlighted the growing seriousness of the problem, with more people living longer and the frequency of depression increasing with age. Kungl. Vetenskapsakademien (2011) estimates the cost of mental illness "to be at least 75 billion SEK per year" and points out that "the funding for psychiatric research corresponds to no more than 0.1-0.2% of the total cost of mental illness, while cancer research receives 2% of the cost of cancer diseases". The causes of depression are only partially understood, and no new treatments have been developed since the 1950s. 25-35% of patients receiving standard antidepressants have only partial or no response. Thus, there is a great need to develop drugs based on new therapeutic principles. We and other researchers have found that an endogenous substance, neuropeptide Y (NPY), is lowered in the brains and livers of depressed patients and that successful treatment raises NPY. Similar results have been obtained in animal models. Taking these facts into account, we want to give NPY to depressed patients in a double-blind study and test its antidepressant effects. Our work is supported by the Swedish Research Council and may open new ways to treat recurrent depression.
Mellstedt, Håkan	Karolinska Institute	ROR1 - novel tyrosine kinase receptor for targeted therapy in tumors	Medicine	2013	Amount granted: SEK 700 000 Chronic lymphocytic leukemia (CLL) expresses the tyrosine kinase receptor ROR1, as do, for example, pancreatic cancer and lung cancer. ROR1 is not found in normal adult cells. ROR1 is essential for the survival of cancer cells and its expression increases with the aggressiveness of the disease. Antibodies have been produced against ROR1, which specifically kill leukemia cells and pancreatic cancer cells. These antibodies kill leukemia cells better than rituximab and ofatumumab, the antibodies that are the standard treatment for CLL. Our antibodies can eliminate leukemia cells in an animal model. We have also produced small chemical molecules, tyrosine kinase inhibitors (TKIs), that specifically recognize ROR1 and kill tumor cells. These drugs have a different mechanism of action than antibodies. We have generated ROR1 TKIs, which can kill leukemia cells more specifically and effectively than fludarabine. They kill 60 times more leukemia cells than normal white blood cells. These ROR TKIs also kill leukemia cells that are resistant to fludarabine. ROR1 TKIs kill pancreatic cancer cells better than gemcitabine. The molecules have promising pharmacological properties. The goal is now to conduct treatment trials in animal models to develop ROR candidates for clinical treatment trials in patients. CLL is a non-curable disease and current treatment options for lung and pancreatic cancer are poor. There is a great need to develop new therapies. ROR1 is a promising structure for developing new targeted therapies against small side effects on normal cells.
Fridberger, Anders	Linköping University	New molecular targets for the treatment of age-related hearing loss	Medicine	2013	Amount granted: SEK 1 400 000 Age-related hearing loss affects around 40% of older people. The condition causes many people significant problems in understanding speech and therefore contributes to exclusion, isolation, depression, and perhaps even the development of dementia. Hearing aids and cochlear implants are helpful but they do not replace normal hearing and most sufferers therefore continue to have significant problems. There is no treatment for the underlying disease. My research team has developed a microscope that allows us to directly observe the inner ear sensory cells when the ear is hit by sound - we can 'see how we hear'. No other group has the technical capability for such experiments and we can thus generate unique data. With the microscope, we have discovered a new mechanism of great importance for hearing. Sensory cells contain stereocilia, whose mechanically sensitive ion channels translate sound waves into electrical signals. We have found that the function of the stereocilia is regulated by the electrical voltage of the surrounding fluid. If the voltage is reduced, the stereocilia become so soft that they no longer function. A low electrical voltage is the most common cause of age-related hearing loss, and our results therefore have direct relevance to the understanding of this condition. This project studies how stereocilia function is regulated at the molecular level. This knowledge is used to develop new treatments for age-related hearing loss.
Gillberg, Christopher	University of Gothenburg	Neurophysiological markers for autism spectrum disorders - a MEG study	Medicine	2013	Amount granted: SEK 1 800 000 Autism spectrum disorder (ASD) is an umbrella term for conditions characterized by problems with social interaction, language comprehension and flexibility. The direct causes of ASD are, in most cases, unknown and there is no physiological test (e.g. blood test) that can identify ASD. Using the latest technology in brain imaging methods (magnetoencephalography, MEG) and individuals with ASD who have undergone thorough clinical examinations, we hope to identify a marker for ASD. Individuals with ASD and control subjects will be shown different images at the same time as brain imaging takes place; when an image is shown, brain activity occurs and this brain activity creates magnetism that MEG registers. It is then possible to see brain activity in real time, i.e. where, when and how long the brain reacts. In MEG, it is also possible to see where on the image the subjects are looking, so we can be sure that the participants in the study are actually looking at the image presented. One of the project leaders in the study is conducting a similar study at Harvard University in America, so we will be able to compare data from both studies and draw stronger conclusions. The project management team consists of individuals with extensive experience in ASD and brain imaging and includes two doctors, a psychologist and a physicist. By the end of this project, we hope to have identified markers that will lead to a better understanding of the underlying physiological mechanisms of ASD.
Erhardt, Sophie	Karolinska Institute	Schizophrenia and its co-morbidities - common pathophysiology?	Medicine	2013	Amount granted: SEK 2 000 000 Schizophrenia is a serious psychiatric disorder that affects about one percent of the population. Patients with schizophrenia have about 30% shorter life expectancy than healthy people. This is largely explained by a high risk of suicide and co-morbidity with cardiovascular diseases (CVD). The drugs currently available can provide some symptom relief, but also increase the risk of further CVD. The need for new medicines that address the pathophysiological cause is therefore enormous! Our recent studies show that low-grade inflammation in the brain of patients contributes to the onset of symptoms. Changes in the immune system also play a central role in the development of CVD and suicidal behavior. Our multi-translational project aims to identify biomarkers in schizophrenia and to study genetic and molecular pathophysiological causes of these. We will study newly diagnosed patients with schizophrenia using advanced brain imaging techniques (PET), analyze central and peripheral levels of immune markers and study pathophysiological mechanisms in patient-specific cell cultures. We will also examine the patients for CVD and suicide risk and study biological risk factors for this comorbidity. The overall goal of our project is to identify pathophysiological mechanisms in schizophrenia and to find reasons for the co-morbidity of CVD and suicidal behavior. This will allow us to propose new pharmacological targets and treatment principles for schizophrenia.
Björck, Lars	Lund University	Harmful and beneficial bacterial proteins	Medicine	2013	Amount granted: SEK 2 000 000 We humans live in a close relationship with different microorganisms and bacteria are the most common cell type in the body, an adult human carries 1-2 kg of bacteria mainly on the skin and in the intestines. This so-called normal flora contributes to a normal and healthy life. At the same time, outside bacteria, but also members of the normal flora, can cause disease. For more than 30 years, we have discovered, purified and studied bacterial proteins that interact in different ways with the human host in which the bacteria live. Many of these proteins have been isolated from streptococci, bacteria that can appear in the throat and on the skin without causing any symptoms of disease, but which also cause mild (tonsillitis, rose fever) and life-threatening infections (sepsis and deep tissue infections). In this project, we want to investigate how some of the streptococcal proteins we have discovered may contribute to severe infections. These include a group of antibody-binding surface proteins (members of the so-called M-protein family) and a protein that the bacteria deliver to the environment (protein SIC). We also want to study an enzyme (IdeS) that cleaves human IgG antibodies with a unique degree of specificity, an activity that allows the bacteria to defend themselves against our immune system. The fact that IdeS only cleaves IgG antibodies and no other protein, on the other hand, has opened an exciting opportunity to treat patients with disease-causing IgG antibodies with this bacterial enzyme.
Ehrsson, Henrik	Karolinska Institute	How do we experience the body as our own? Research on cortex mechanisms	Medicine	2013	Amount granted: SEK 2 600 000 Bend your head forward and look down at your body. You see two arms, two legs, a stomach and a chest. But how does the brain understand that this body is your own? In our research project, we will use the most advanced brain imaging and brain stimulation techniques to answer this question. Our hypothesis is that the whole-body experience is created by two parallel cortex mechanisms. Signals from vision, touch and muscle sense are integrated in specific areas of the frontal lobe and the association cortex of the cerebral lobe to create the experience of a single coherent body, while processes in the temporal lobe generate signals about the location of this body in space. We will then go on to show that this brain's internal representation of the body affects episodic memory - one of our most important higher cognitive functions. Our hypothesis is that episodic memory requires us to have a functioning whole-body experience, and that disturbances in this, such as in "out-of-body experiences", lead to disrupted memory storage by affecting the temporal lobe memory area. In summary, our results will provide a groundbreaking description of the cortex mechanisms underlying whole-body spatial perception, and also demonstrate for the first time that this perception affects our episodic memory. These results may lead to important new advances in applied research on virtual reality, cognitive psychiatry and advanced prosthetics.
Engel, Jörgen	Sahlgrenska Academy	Role of gastrointestinal hormones in the development of addiction disorders	Medicine	2013	Amount granted: SEK 1 000 000 Alcohol dependence is a chronic disease that affects about 3 to 8% of the population. It causes great suffering for the individual and relatives and is a major social problem. This complex disease involves an annual cost of approximately SEK 150 billion in Sweden and there is a great need to develop adequate treatment strategies. Our and others' research has shown that alcohol interacts with brain neurotransmitters in a very complex way. The goal of our translational research is to increase the understanding of the mechanisms involved in alcohol dependence and to create the conditions for the development of new and better drugs. Recently, we have shown that the appetite-stimulating peptide ghrelin and its receptor are potential targets for the development of new treatment strategies for alcohol dependence. This is a completely new approach to research on alcohol addiction and its treatment and may provide new ideas for drugs to treat drug addiction. We are now investigating whether ghrelin and its receptor are important for several aspects of alcohol dependence such as relapse, motivation and drug craving. The possibility that alcohol interacts directly with the ghrelin receptor and causes epigenetic changes is also being studied. Genetic changes in genes expressing ghrelin and its receptor are being investigated in populations with different addiction states. This knowledge is of utmost importance for the development of new pharmacological agents for the treatment of addiction disorders.

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