Mechanisms of Innate Immune Regulation for Mucosal Homeostasis These studies will provide new insights into the integration of innate immune activation pathways required for the recognition of microbiota at mucosal surfaces. We have identified the guanine nucleotide exchange factor H1 (GEF-H1) encoded by the arhgef2 gene as a required component of innate immune regulation by CARD-domain containing NOD-like receptors. We hypothesize that GEF-H1 is a required signaling intermediate from which signals diverge to control either inflammatory or inhibitory immune responses during microbial pattern recognition. We will define key mechanisms that allow GEF-H1 to regulate innate immune responses by regulating receptor-interacting serine/threonine-protein kinases (Rips) and examine the protein domains and post-translational modifications of GEF-H1 responsible for the control of immune activation and suppression by microbial factors. Defining the functional role of this newly discovered central component of microbial pattern recognition will provide pivotal insights into the mechanisms that mediate mucosa specific control of innate immune responses and tissue repair in the highly antigenic environment of the intestine.
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 mucosal host defenses to regulate immune responses during microbial pattern recognition. The elucidation of the biology of this critical signaling intermediate will provide pivotal insights into the genetic basis of Crohn?s disease leading to mucosal inflammation and the mechanisms that are required for intestinal tissue repair.
