Intestinal Mucosal Growth in Health & Surgical Diseases

描述(由申请人提供)：肠粘膜生长抑制通常发生在各种严重的外科疾病中，如创伤、休克和大规模外科手术。由于我们对这一关键病理过程背后的机制缺乏了解，因此在外科危重疾病患者中维持黏膜上皮完整性的有效治疗方法有限，导致黏膜萎缩、愈合延迟、屏障功能受损和细菌易位。近年来，转录后事件，尤其是改变的mRNA翻转和翻译，在胃肠道粘膜基因表达程序的调控中的重要作用越来越被人们所认识，但对于它们在关键手术条件下粘膜生长抑制的发病机制中的重要性却知之甚少。基于我们在上一个资助期的重大进展和令人兴奋的初步研究，在这次竞争性更新申请中提出的实验是为了验证这样一种假设，即RNA结合蛋白CUGBP1通过改变其编码生长调节蛋白的目标mRNAs的表达而在肠粘膜生长调节中发挥重要作用，其作用受给定的microRNAs和细胞多胺的调节。为了检验这一假说，本文提出了三个具体目标。1)确定CUGBP1在关键手术条件下调节肠粘膜生长中的确切作用，并进一步确定其靶向mRNAs。2)确定microRNAs和CUGBP1是否共同调节靶mRNAs在手术应激下的稳定性和翻译。3)明确多胺调节CUGBP1表达和microRNA生物发生的机制。这些特定目标的完成将揭示CUGBP1和microRNAs在肠粘膜生长抑制的发病机制中的新功能，并将影响改进肠粘膜萎缩患者的治疗方法的努力。希望这些研究将确定潜在的治疗靶点和制剂，这些靶点和制剂可能在未来用于维持外科危重疾病患者的肠道粘膜完整性。 公共卫生相关性：急性肠黏膜生长抑制通常发生在各种危重外科疾病中，如创伤、热损伤、休克、败血症和大规模外科手术。由于黏膜生长抑制的确切机制尚不清楚，因此在外科危重疾病患者中保持上皮完整性的有效治疗方法有限，导致黏膜萎缩、愈合延迟、屏障功能受损和细菌移位。该项目的完成将确定在关键外科条件下这一关键病理过程背后的分子机制，并为开发新的治疗方法以增强外科危重疾病患者的粘膜上皮更新提供基本基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.