Project Summary/Abstract 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 >240 loci associated to IBD, a number of genes modulate host PRR responses at many levels and confer some of the largest genetic effects observed in autoimmunity. Despite the significant recent discoveries in IBD-associated genetics, the functional consequences of the majority of the genetic loci have yet to be identified. A central outcome of PRR activation by microbial products is induction of cytokine and microbial clearance pathways. Further, IBD is largely characterized by dysregulated cytokines and anti-microbial responses, and the inter-individual variation in PRR-induced outcomes influences the disease susceptibility. We hypothesize that polymorphisms in multiple IBD-associated genes contribute to inter-individual variation in PRR-induced cytokine and microbial clearance pathways, and that we will be able to more clearly classify individuals in the context of this dichotomy. Systematic, well-powered studies comprehensively defining the functional alterations driven by disease-associated human variation can provide enormous insight into central mechanisms of IBD; leveraging naturally occurring human genetic variation to systematically “perturb” an experimental system represents an advantageous approach for precisely defining established and novel PRR-mediated mechanisms mediating the balance between cytokine secretion and microbial clearance. Therefore, we will utilize a large, well-powered cohort to screen for IBD-associated polymorphisms contributing to the variation in PRR-initiated cytokine secretion and microbial clearance across individuals and then define the molecular mechanisms wherein the implicated IBD-associated genes, as well as the identified polymorphisms, regulate PRR-induced outcomes. Relevance These combined studies will provide insight into whether those IBD-associated loci that regulate PRR- induced cytokine secretion and bacterial clearance do so through a loss- or gain-of-function, the mechanisms wherein the implicated genes mediate their contributions to these PRR-induced outcomes, and the specific consequences of the polymorphisms on gene function through examination of monocyte- derived cells from selected carriers. These comprehensive and mechanistic studies will be crucial for future studies that will examine gene consequences in vivo and ultimately, for improved disease classification and therapeutic targeting.