Inhibition of intestinal mucosal growth occurs commonly in various critical surgical disorders such as trauma, shock, and massive surgical operations. Because our deficient understanding of the mechanism underlying this critical pathological process, effective therapies to maintain the mucosal epithelial integrity in patients with critical surgical illnesses are limited, leading to mucosal atrophy, delayed healing, impaired barrier function, and bacterial translocation. Recently, the essential contribution of posttranscriptional events, particularly altered mRNA turnover and translation, in the control of gene expression program in the GI mucosa is becoming increasingly recognized, but little is known about their importance in the pathogenesis of mucosal growth inhibition in critical surgical conditions. Based on our significant progress during the previous funding period and exciting preliminary studies, experiments proposed in this competitive renewal application are to test the HYPOTHESIS that the RNA-binding protein CUGBP1 plays an important role in the regulation of intestinal mucosal growth by altering expression of its target mRNAs encoding growth-regulatory proteins and its effect is regulated by given microRNAs and cellular polyamines.
Three specific aims are proposed to test the hypothesis. 1) To determine the exact role of CUGBP1 in the regulation of gut mucosal growth in critical surgical conditions and to further identify its target mRNAs. 2) To determine whether microRNAs and CUGBP1 jointly regulate the stability and translation of target mRNAs in response to surgical stress. 3) To define the mechanisms by which polyamines regulate CUGBP1 expression and microRNA biogenesis. Completion of these specific aims will uncover novel functions of CUGBP1 and microRNAs in the pathogenesis of gut mucosal growth inhibition and will impact upon efforts to improve therapeutical approaches for patients suffering gut mucosal atrophy. It is hoped that these studies will identify potential therapeutic targets and agents which could be used in the future to maintain intestinal mucosal integrity in patients with critical surgical illnesses.
Acute gut mucosal growth inhibition occurs commonly in various critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations. Since the exact mechanisms underlying mucosal growth inhibition are still obscure, effective therapies to preserve the epithelial integrity in patients with critical surgical illnesses are limited, contributing to mucosal atrophy, delayed healing, impaired barrier function, and bacterial translocation. Completion of this project will identify the molecular mechanism underlying this critical pathological process in critical surgical conditions and provide a fundamental base for development of new therapies to enhance mucosal epithelial renewal in patients with critical surgical illnesses.
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