Descripción del proyecto
Multiple Sclerosis (MS) is a leading cause of unpredictable and incurable progressive disability in young adults. Although the exact cause remains unknown, this immune-mediated disease is likely triggered by environmental factors in genetically predisposed individuals. I propose that epigenetic mechanisms, which regulate gene expression without affecting the genetic code, mediate the processes that cause MS and that aberrant epigenetic states can be corrected, spearheading the development of alternative therapies. We will exploit the stable and reversible nature of epigenetic marks, in particular DNA methylation, to gain insights into the novel modifiable disease mechanisms by studying the target organ in a way that has not been possible before. This highly ambitious project comprises three synergistic facets formulated in specific aims to: (i) identify epigenetic states that characterize the pathogenesis of MS, (ii) prioritize functional epigenetic states using high-throughput epigenome-screens, and (iii) develop novel approaches for precision medicine based on correcting causal epigenetic states. Our unique MS biobank combined with cutting-edge methodologies to capture pathogenic cells and measure their functional states provides a rational starting point to identify MS targets. I will complement this approach with studies of the functional impact of MS targets using innovative in vitro screens, with the added value of unbiased discovery of robust regulators of specific MS pathways. Finally, my laboratory has extensive experience with animal models of MS and I will utilize these powerful systems to dissect molecular mechanisms of MS targets and test the therapeutic potential of targeted epigenome editing in vivo. Our findings will set the stage for a paradigm-shift in studying and treating chronic inflammatory diseases based on preventing and modulating aggressive immune responses by inducing self-sustained reversal of aberrant epigenetic states.