Small non-coding RNA profiling across cellular and biofluid compartments and their implications for multiple sclerosis immunopathology

• Stockholm County Council

• Swedish Brain Foundation

• Swedish Association of persons with Neurological disabilities

• AstraZeneca-Science for Life Laboratory collaboration

• Swedish Research Council

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  ROR

2017-00777_VR

Genetics and Pathogenesis of neuroinflammation with a focus on Multiple Sclerosis

In multiple sclerosis (MS), inflammatory cells from the blood periodically enter the central nervous system, where they cause damage to nerve tracts and neurological deficits. With time, MS becomes progressive with increasing disabilities. Current treatments are risky because they strike broadly in the immune system, and there are no therapies for the progressive phase. The etiology of MS involves both genetic predisposition and lifestyle/environmental factors, thus logically targets for studies.The overall aim is to understand the causes, pathogenesis and severity/progression of MS by studies in very large, nation-wide, MS case-control materials, integrated with molecular genetics and functional studies in materials from humans and in rodent models of MS.  The project is multidisciplinary and relies on intensive local, national and international collaborations.We will: 1) Define gene loci, lifestyle/environmental factors and pathways that drive severity/progression, in addition to MS risk alone. 2) Decipher MS risk gene-environment interactions. We have shown that such interactions are potent, and we are world-wide leading these attempts. 3) Define the function of selected MS gene loci. 4) Define the disease relevant T cell specificities with a new technology. 5) Study the mechanisms of selected genes/loci regulating mouse and rat MS mimicking models.The project can lead to a better prevention, and to a basis for more precise treatment during the different phases of MS.

• Horizon 2020

• Swedish Society for Medical Research

• Swedish Research Council

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  ROR

2018-02638_VR

Epigenetics of Multiple Sclerosis: towards a better understanding of pathogenic mechanisms and improved disease management

Multiple Sclerosis (MS) is a leading cause of incurable progressive neurological disability in young adults. We propose that epigenetic mechanisms such as DNA methylation, that regulate gene expression without affecting the genetic code, mediate the processes that cause MS and that aberrant epigenetic states can be corrected to develop alternative therapeutic modalities.We will exploit the stable and reversible nature of DNA methylation to: (i) Identify novel modifiable mechanisms that trigger MS and predispose for disease progression, (ii) Develop alternative therapeutic strategies based on reversing causal epigenetic states, and (iii) Characterize epigenetic marks that can serve as specific biomarkers. Our unique MS biobank combined with cutting-edge methodologies to capture relevant cells and measure their functional states from the full methylome and transcriptome data provides a starting point to identify aberrant epigenetic changes in MS. This will be complemented with studies of the functional impact of these changes using innovative in vitro epigenome screens. We will then utilize in vivo animal models to dissect their molecular mechanisms and test the therapeutic potential of targeted epigenome editing.Our findings may set the stage for a paradigm-shift in studying and treating chronic diseases based on preventing and modulating aggressive immune responses and promoting brain tissue repair through inducing self-sustained reversal of aberrant epigenetic states.

• Swedish Research Council

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  ROR

2014-03124_VR

An epigenomic approach to identify key drivers of chronic inflammation and neuronal loss in Multiple Sclerosis

Predisposition to common diseases irrefutably depends on the complex interplay between genes and environmental factors. Despite the fact that epigenetic mechanisms (e.g. DNA methylation) control gene expression following instructions from the genome and environment, they are still virtually unexplored in diseases such as Multiple Sclerosis (MS). We will (i) exploit epigenetic changes to learn more about the mechanisms that mediate effects of genetic and environmental factors in etiology of MS; (ii) characterize epigenetic changes that control ´aggressiveness´ of the pathogenic cells (CD4+ T cells and monocytes) and ´vulnerability´ of the target cells (neurons); (iii) define functional mechanisms of the most interesting changes; and (iv) investigate if the obtained knowledge can be used for better biomarkers and novel treatments. We will utilize unique and world-renowned clinical cohorts in combination with state-of-the-art methods to measure DNA methylation and transcription in discrete cell types, followed by functional studies in experimental models. The vital difference between genetics and epigenetics lies in the fact that epigenetic states are reversible and it is possible to alter unfavorable state towards recovery. Therefore, characterizing epigenetic mechanisms gives tremendous opportunities for better understanding and management of MS and can have important implications for other diseases with similar complex etiologies.