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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01DK033506-29
Application #
8727518
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
Budget End
Support Year
29
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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