The pathogenic role of poly (ADP-ribose) polymerase 1 (PARP-1) in experimental co

University Of Arizona, Tucson AZ

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Abstract

DESCRIPTION (provided by applicant): Poly (ADP-ribose) polymerases (PARPs) constitute a family of 18 cell signaling enzymes, which are involved in the regulation of DNA-binding proteins and DNA repair. These enzymes catalyze the transfer of ADP-ribose units from NAD+ to a number of acceptor proteins (by a process called poly (ADP) ribosylation) and can also interact directly with their target proteins. Among the PARPs, PARP1 is the most abundant isoform and has been described to regulate the expression of diverse proinflammatory mediators, through its interaction with numerous transcription factors such as NF-kB and AP-1. Recent published observations (including our group) suggest that PARP-1 is a cofactor for NF-kB-dependent gene expression. Several studies in Parp1 KO mice have shown a decreased expression of host inflammatory mediators, cytokines, chemokines, adhesion molecules as well as reduced immune tissue infiltration in various model of inflammation including, streptomycin induced diabetes, LPS induced septic shock, ischemia and reperfusion injury. Interestingly, in vivo studies have demonstrated that genetic ablation or pharmacological inhibition of PARP1 ameliorates the pathophysiological changes of experimental colitis. However, the studies published to date have failed to characterize the exact mechanism by which PARP1 inhibition is protective in colitis and in which cell type PARP1 inhibition would have the most significant impact in IBD. Such studies are critical in guiding future development of therapeutics targeting PARP1, with proper pharmacokinetics and pharmacodynamics. Our preliminary data obtained with adoptive T-cell transfer model of colitis indicate that Parp1 is dispensable in T-cells, while Parp1-/- mice are protected from colitis resulting from epithelial damage induced by DSS. These data collectively suggests that the pathogenic role of Parp1 in colitis is restricted to either colonic epithelial cells or other cells of the innate immune system. A novel mouse model for conditional cell-type specific Parp1 targeting, Parp1/Rag1 double knockout mice, and bone marrow chimeras developed as part of this proposal will be used in the following specific aims: (1) we are planning to differentiate the pathogenic role of PARP1 in hematopoietic or parenchymal cells in the development of colitis, (2) to investigate the role of Parp1 deletion in intestinal epithelial cells and (3) to characterize the role of PARP1 on neutrophil and macrophage functions. Those specific aims will help address the following hypothesis: PARP1 contributes to aggravated mucosal immune response via modulation of inflammatory signaling pathways within the cells of the innate immune system.