ARRA: Novel in vivo models for cell-type specific MyD88 signaling in the intestine

Innate and acquired immune responses in the intestine must promote homeostasis in the presence of large numbers of commensal microorganisms, while maintaining the capacity to defend the body against invasive pathogens. I-lost cells recognize microorganisms through pattern recognition molecules including Toll-like receptors (TLRs), which bind microbial cell wall constituents, nucleic acids and other by-products. MyDBB is a cytoplasmic adaptor protein that transduces signals emanating from TLRs. Recent studies have demonstrated that mice genetically deficient in MyDBB expression are more sensitive to experimental colitis than are wild-type mice, suggesting a key role for TLR signaling in regulation of intestinal inflammation. Our preliminary data demonstrate that MyDB8-deficient mice have severely depressed expression of the polymeric immunoglobulin receptor (plgR), a key anti-inflammatory molecule that mediates epithelial transport of protective IgA antibodies. The goal of the parent project was to generate novel mouse models for studying epithelial-specific MyD8B signaling within the intact intestine. We proposed to generate novel chimeric and transgenic mouse models in which MyDS8 expression is restricted to epithelial cells or bone marrow-derived cells. We are now poised to test the clinical and molecular responses of these mice to inflammatory stimuli in a model of experimental colitis. I plan to request a 1-year no-cost extension of the parent project to allow sufficient time to complete these analyses. Because the project is moving into a labor-intensive phase, we are requesting an administrative supplement to hire 2 additional staff, including a PhD student and a laboratory technician. Funds requested will specifically be directed to NIH Areas of Interest, including research employment opportunities for pre-doctoral students and research employment opportunities for recent college graduates.