Intestinal Mucosal Growth in Health & Surgical Diseases

描述（由申请人提供）：肠粘膜生长抑制常见于各种严重的外科疾病，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，因此在严重外科疾病患者中维持粘膜上皮完整性的有效治疗受到限制，导致粘膜萎缩、愈合延迟、屏障功能受损和细菌易位。最近，人们越来越认识到转录后事件，特别是mRNA转换和翻译的改变，在胃肠道粘膜基因表达程序的控制中所起的重要作用，但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。基于我们在之前资助期的重大进展和令人兴奋的初步研究，本次竞争性更新申请提出的实验是为了验证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，其作用受给定的microRNAs和细胞多胺的调节。为了验证这一假设，提出了三个具体目标。1)确定CUGBP1在外科危重条件下调控肠黏膜生长中的确切作用，并进一步鉴定其靶mrna。2)确定microRNAs和CUGBP1是否在手术应激下共同调控靶mrna的稳定性和翻译。3)明确多胺调控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microrna在肠黏膜生长抑制发病机制中的新功能，并将影响改善肠黏膜萎缩患者的治疗方法。希望这些研究能够确定潜在的治疗靶点和药物，以便在未来用于维持外科危重疾病患者的肠黏膜完整性。

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.