The interplay between microbial and genetic susceptibility factors is central to the development of inflammatory bowel disease (IBD). Innate mechanisms, in particular through pattern recognition receptor (PRR) pathways, are the initiating drivers of host responses to microbes. Of the 163 loci associated to IBD, a broad range of likely genes modulate host responses to PRR at many levels, and confer some of the largest genetic effect sizes observed in autoimmunity. Despite the significant discoveries in IBD-associated polymorphisms over the past few years, the functional consequences of the vast majority of these loci have yet to be identified. A central outcome of PRR activation by bacterial and viral products is induction of cytokine secretion. To a large extent, IBD is characterized by dysregulated cytokines, and modulation of cytokines plays a primary role in IBD treatment. Inter-individual variation in PRR- induced cytokine secretion influences the balance between susceptibility to infection and inflammatory diseases. We hypothesize that polymorphisms in multiple IBD-associated genes contribute to inter-individual variation in PRR-induced cytokine secretion. Systematic, well- powered studies comprehensively defining the functional alterations driven by disease- associated human variation will provide enormous insight into central mechanisms of IBD; leveraging naturally occurring human genetic variation to systematic perturb an experimental system represents a highly innovative approach for precisely defining established and novel PRR-mediated mechanisms of cytokine secretion. Therefore, we will utilize a large, well- powered cohort to screen for IBD-associated polymorphisms contributing to the variation in PRR-initiated cytokine secretion across individuals, and then define the molecular mechanisms wherein the implicated IBD-associated genes, as well as the identified polymorphisms, regulate PRR-induced cytokine secretion.
We have developed a large functional screen to dissect the contributions of inflammatory bowel disease (IBD)-associated polymorphisms to the variation between individuals in pattern recognition receptor (PRR)-induced cytokine secretion; this provides a uniquely powerful means of determining the functional consequences of a number of IBD-associated loci. We will utilize this screen to first identify those IBD-associated polymorphisms contributing to PRR-initiated cytokines, and then dissect the mechanisms wherein both the genes and the specific polymorphisms within the genes modulate PRR-initiated cytokine secretion. Given the primary role that modulation of cytokine expression has played thus far in the treatment of IBD, we anticipate that studies focused on disease-associated polymorphisms that modulate cytokine secretion will ultimately result in the improved targeting and prioritization of new therapeutic targets for IBD.
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