Defective regulation of early intestinal mucosal restitution underlies various critical pathological states such as acute mucosal injury/hemorrhage, impaired repair of erosions/ulcers, disruption of epithelial integrity, and epithelial barrier dysfunction. Since the exact mechanisms of early rapid mucosal restitution after superficial wounds are still obscure, effective therapies to preserve gut epithelial integrity in clinic are limited, especially in patiets with critical surgical illnesses such as trauma and sepsis. The restoration of normal intestinal mucosal integrity after injury and/or ulceration requires epithelial cell decisions that regulate signaling networks controlling expression of various genes. Posttranscriptional events, particularly altered mRNA turnover and translation, are major mechanisms by which mammalian cells control gene expression in response to various stresses. Changes in mRNA stability and translation are predominantly governed by RNA-binding proteins (RBPs) and microRNAs (miRNAs) that are emerged as master regulators of maintenance of gut epithelial integrity. However, little is known about the roles of RBPs and miRNAs in the mechanisms underlying rapid mucosal restitution after acute injury. HuR is among the most prominent translation and turnover regulatory RBPs and is recently show to regulate cell motility. Our preliminary results indicate that a) HuR silencing represses intestinal epithelial cell (IEC) migration over the wounded area in an in vitro model; b) tissue specific HuR knockout inhibits early intestinal mucosal repair after injury; and c) miR-195 overexpression represses early epithelial repair in vitro, but this repression is rescued by increasing HuR levels. Based on these exciting observations, we HYPOTHESIZE that HuR is essential for intestinal epithelial restitution after injury by altering the stability and translation of target mRNAs encoding cell migration-regulatory proteins and its effect is regulated by given miRNAs.
Three specific aims are proposed to test the hypothesis. 1) To determine the exact role of HuR in early intestinal mucosal restitution after acute injury. 2) To define new target mRNAs of HuR and its role in the regulation of mRNA stability and translation in the intestinal epithelium after wounding. 3) To investigate the interactions between HuR and given miRNAs in the control of stability and translation of target mRNAs in response to epithelial injury. Completion of these specific aims will make a significant conceptual advance by linking HuR/miRNA-mediated posttranscriptional gene regulation with early mucosal restitution in the intestine and will create a fundamental base for development of new therapeutic approaches for gut mucosal injury-related diseases and for maintaining epithelial integrity under various clinical conditions.
Early mucosal restitution is an important primary repair modality in the gastrointestinal (GI) trat and its defective regulation underlies various GI mucosal injury-associated disorders. These disorders occur commonly and are major health issues in our veteran population. However, the effective therapies for preventing gut mucosal injury and for enhancing mucosal repair in clinic are limited to date. Thus, improving the understanding of the process by which gut mucosa repairs itself rapidly after acute injury is the first step towards therapeutic initiatives in thisarea. Based on our long-term interest and exciting preliminary results, studies proposed here are to determine the roles and mechanisms of RNA-binding protein HuR and microRNAs in the regulation of GI mucosal restitution after acute injury. Completion of these experiments will provide supportive data to strengthen our long-term goal that is to develop more effective therapeutic approaches for GI mucosal injury-related diseases for our VA patients.
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