PARP1 and PARylation as novel effectors of gut inflammation

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Despite recent advances in the understanding host-microbiome interactions in the pathogenesis of Inflammatory Bowel Diseases (IBD), the complexity of the host’s response to changing gut microbiota is daunting and still incompletely understood. In this proposal, we show that poly-ADP-ribosylation (PARylation), a post-translational modification that involves the enzymatic transfer of ADP-ribose (ADPr) from NAD+ to specific amino acids of target proteins, plays key roles as a mediator of inflammatory response in the gut. For the first time, we provide evidence that PARP1 is the primary PAR writer in the colon, where it serves as a powerful transcriptional modulator. Commensal bacteria are necessary for mucosal PARP1 activity and PARylation and, reciprocally, PARP1 controls the microbial composition and metabolic activity, modulates colonic epithelial barrier function, and restricts the mucosal Treg compartment. Importantly, human and murine colitis is associated with mucosal hyperPARylation, which can be transferred to germ-free mice with complex microbial community from IBD patients. Total or epithelial-specific knockout of PARP1 (or pharmacological inhibition) protect from and promote recovery from mucosal injury. Based on these novel preliminary observations, we hypothesized that hyperPARylation is a significant contributor to mucosal inflammation and impaired mucosal restitution via both extrinsic (interaction with gut microbiota) and intrinsic effects in the colonic mucosa. We will address this hypothesis in the following three well-integrated, but not mutually contingent specific aims, which will: (1) Define the role of NAD+ depletion vs. hyperPARylation as putative culprits in the pathogenesis of experimental colitis (2) Define the role of PARP1 and PARylation in colitis mediated by human IBD microbiota; and (3) Mechanistically define the roles of PARP1 in the highly interactive relationship between gut microbiota and epithelial barrier function and mucosal restitution.in the inflamed colon. This novel research plan will greatly advance the field of fundamental mucosal biology and will offer targeting of PARP1 activity as a potential IBD therapy.