Macrophage Gene Expression in Mucosal Inflammation

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DESCRIPTION (provided by applicant): NOT-OD-09-058 NIH Announces the Availability of Recovery ct Funds for Competitive Revision Applications. This is a competitive supplemental application to the parent R01, 2 R01 DK054452, "Macrophage Gene Expression in Mucosal Inflammation". It is based on abundant preliminary results obtained under the auspices of the parent grant which moves this project into a completely new direction. Recently described of susceptibility genes in human Crohn's disease (CD) highlight innate immune interactions with the enteric microbiota as critical events in disease pathogenesis. Specifically, the CD susceptibility genes CARD15, ATG16L1, and IRGM all have important roles in host-microbial responses; including sensing of microbial; products, production of antimicrobial peptides, and intracellular killing of bacteria. In the parent R01, Specific Aims 3 and 4 elucidate the molecular pathogenesis of spontaneously occurring colitis in a novel mouse model of IBD, genetically engineered mice mutant in the p1104 subunit of phosphatidyl inositol-3-kinase (PI3K). Experiments completed in the parent grant demonstrate that macrophages from PI3K p110D910A/D910A mutant mice are hyper-responsive to toll-like receptor signaling, and defective in their capacity to downregulate inflammatory responses in the presence of anti-inflammatory mediators such as IL-10. Although these findings help explain chronic intestinal inflammation mediated by IL-12/23, Th1, and Th17 cytokines described by our experiments, recent results also show that macrophages from PI3K p110D910A/D910A mutant mice have attenuated bactericidal activity against enteric bacteria. This unanticipated result 1) suggests that this mouse model may provide an important reagent for understanding the pathogenesis of human CD, and 2) leads to an entirely new area of research that was not part of the aims of the original scientific proposal. We therefore embark upon a new, significant scientific direction for the laboratory with direct relevance to CD. We propose to characterize at the molecular level how the PI3K p1104 subunit modulates bactericidal activity in macrophages. To accomplish these aims, we have established new collaborations and it is necessary to recruit new talent to the laboratory to further develop the expertise and technologies to answer these questions. PUBLIC HEALTH RELEVANCE: This supplement will accelerate scientific discovery about the pathogenesis of the human IBDs which affect over 1,000,000 U.S. citizens. This supplement is expected to stimulate the economy by: Enabling increased hours of current part-time staff. The position of the sole support on this project will otherwise be terminated. This will also support experiments in germ- free mice in conjunction with the National Gnotobiotic Rodent Resource Center.