These studies will provide new insights into the integration of innate immune activation pathways required for the recognition of microbiota at mucosal surfaces, a thematic goal shared between Project 1 and Project 4. In collaboration with Project 3, GEF-Hl was identified as an unexpected essential component of innate immune regulation. GEF-Hl functioned as part of Rip2 containing signaling complexes and was required for the induction of tyrosine phosphorylation of Rip2 essential for NF-KB activation. We will determine key mechanisms that allow GEF-H1 to mediated innate immune activation by regulating receptor-interacting protein (RIP) family kinases and non-receptor tyrosine kinases and examine the protein domains and posttranslational modifications of GEF-H1 responsible for the control of innate immune responses to microbial factors. New preliminary data obtained in work with Project 2, demonstrate that GEF-Hl further controls the activation of inflammatory pathways by the corticotropin receptors CRHR1 and CRHR2. In collaboration with Project 2, we will define the mechanisms by which GEF-H1 mediates neuropeptide dependent regulation of innate immune responses. In collaboration with Project 5 and supported by the isograft and xenograft model systems of Core B, we will determine whether inhibition of GEF-H1 effectors is a promising strategy for the promotion of mucosal recovery from intestinal inflammation.
A more precise definition of the mechanisms of microbial recognition pathways regulating innate first line immune defenses is required for the understanding of the basis of inflammatory bowel diseases. We will define key mechanisms that allow a newly discovered mediator of host defenses to regulate mucosal inflammation and intestinal tissue repair.
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|Ganguli, Kriston; Collado, Maria C; Rautava, Jaana et al. (2015) Lactobacillus rhamnosus GG and its SpaC pilus adhesin modulate inflammatory responsiveness and TLR-related gene expression in the fetal human gut. Pediatr Res 77:528-35|
|Meng, Di; Zhu, Weishu; Shi, Hai Ning et al. (2015) Toll-like receptor-4 in human and mouse colonic epithelium is developmentally regulated: a possible role in necrotizing enterocolitis. Pediatr Res 77:416-24|
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