Acute gut mucosal injury occurs commonly in various critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations. Since the exact mechanisms underlying mucosal injury and repair are still obscure, effective therapies to preserve the epithelial integrity in patients with critical surgical illnesses are limited, contributing to acute mucosal injury, delayed healing, impaired barrier function, and bacterial translocation. During previous funding period, we have established that the transcription factor c-myc and other growth-related proteins play an important role in epithelial cell renewal during mucosal healing and have identified a novel mechanism through which polyamines modulate c-myc expression in critical surgical conditions. However, the upsteam signaling initiating c-myc transcription after injury and how polyamines are implicated in c-myc expression remain unclear and are the focus of this competitive renewal application. Our preliminary results indicate that a) Wnt signaling is activated after mucosal injury, which exhibits a similar pattern of c-myc expression;b) knockdown of Wnt receptors represses epithelial repair;and c) polyamines modulate RNA-binding proteins TIAR and HuR that are involved in translational control of their target mRNAs. Based on these observations, we HYPOTHESIZE that 1) Wnt signaling plays a key role in mucosal healing by stimulating c-myc transcription and 2) increased polyamines following injury regulate c-myc mRNA translation by altering TIAR and HuR.
Three specific aims are proposed to test the hypotheses. 1) To determine the exact role of Wnt signaling in c-myc expression and mucosal healing after injury. 2) To define the mechanism by which Wnt activation enhances c-myc transcription during mucosal healing. 3) To investigate the mechanism by which polyamines regulate c-myc translation during healing. Completion of these specific aims will identify the up stream signals initiating c-myc transcription after mucosal injury and also yield a novel model in which c-myc mRNA translation is regulated by polyamines during healing. It is hoped that our findings will identify factors and mechanisms that can be used to preserve epithelial integrity and enhance mucosal healing in patients with critical surgical illnesses. Project Narrative: Acute gut mucosal injury occurs commonly during various critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations. Since the exact mechanisms underlying mucosal injury and repair are still obscure, effective therapies to preserve the epithelial integrity in patients with critical surgical illnesses are limited, contributing to acute mucosal injury, delayed healing, impaired barrier function, and bacterial translocation. Completion of this project will identify the molecular mechanism underlying mucosal injury and repair in critical surgical conditions and provide a fundamental base for development of new therapies to protect the gut mucosa and enhance healing in patients with critical surgical illnesses.
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