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的机制缺乏了解，维持危重外科疾病患者粘膜上皮完整性的有效疗法有限，导致粘膜萎缩、愈合延迟、屏障功能受损和细菌移位。近年来，越来越多的人认识到转录后事件，特别是改变mRNA的周转和翻译，在控制基因表达程序在胃肠道粘膜的重要贡献，但很少有人知道他们的重要性，在发病机制中的粘膜生长抑制在关键的手术条件。基于我们在之前的资助期间取得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测试以下假设：RNA结合蛋白CUGBP1通过改变其编码生长调节蛋白的靶mRNA的表达在调节肠粘膜生长中起重要作用，并且其作用受到给定的microRNA和细胞多胺的调节。提出了三个具体目标来检验这一假设。1)确定CUGBP1在关键手术条件下调节肠粘膜生长的确切作用，并进一步鉴定其靶mRNA。2)确定microRNA和CUGBP1是否共同调节靶mRNA的稳定性和翻译以响应手术应激。3)确定多胺调节CUGBP1表达和microRNA生物合成的机制。这些特定目标的完成将揭示CUGBP1和microRNA在肠道粘膜生长抑制发病机制中的新功能，并将影响改善肠道粘膜萎缩患者治疗方法的努力。希望这些研究将确定潜在的治疗靶点和药物，可用于在未来维持肠粘膜完整性的危重外科疾病患者。

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.