This proposal focuses on NOD-mediated innate immuny signaling and specifically examines the role of
adaptor proteins in regulating RIP2 functions. RIP2 ubiquitination plays a central role in activating and limiting
the NOD signaling pathways and we recently identified NRAGE as a negative regulator of the NOD innate
immune response. The main goal of this proposal is to characterize the physiological role of NRAGE in
NOD/RIP2 signaling pathways and to potentially identify NRAGE as a component of a multiprotein E3 ligase
complexe that regulates RIP2 ubiquination. This work will integrate the biochemical characterization of the
NRAGE/NOD/RIP2 signaling complex, the identification of the signaling pathways regulated by NRAGE
downstream of the NOD receptors, and test the in vivo relevance of NRAGE in NOD/RIP2 innate immunity
using NRAGE deficient mice challenged with NOD specific agonists. Because defects in NOD signaling
pathways have been tightly associated with Inflammatory Bowel disease in human patients, mouse model of
colitis will be used to potentialy identify NRAGE as a new target for treatment of colitis.