Posttranscriptional Control of Gut Mucosal Defense and Homeostasis

肠上皮的完整性被破坏在各种病理中很常见。 例如炎症性肠病(IBD)和外科重症监护患者 全肠外营养(TPN)，易使粘膜发生破坏性炎症并导致 细菌移位到血液中。因为控制肠道的确切机制 上皮细胞动态平衡仍不清楚，有效的治疗方法保存粘膜上皮 慢性炎症和急性危重病患者的完整性是有限的。 转录后事件，特别是信使核糖核酸(信使核糖核酸)翻转和 翻译，是哺乳动物细胞控制基因表达的主要机制 对各种压力的反应。控制信使核糖核酸的稳定性和翻译 由RNA结合蛋白(RBPs)和非编码RNA(NcRNAs)(包括microRNAs)控制 和长的ncRNA。HU-抗原R(HUR)是最突出的翻译和翻译 监管限制性商业惯例，最近成为上皮完整性的主要调节者 肠子。自噬是细胞对许多不需要的细胞质的降解系统 成分和细胞内病原体；它对细胞、组织和器官是必不可少的 动态平衡。自噬途径越来越被认为是一种重要的机制。 调节肠上皮的防御和动态平衡 病理生理过程。然而，HUR在自噬调节中的确切作用 肠粘膜中的激活仍不清楚，这是当前提案的重点。 我们的初步结果表明：a)肠上皮组织特异性缺失HUR 破坏自噬并导致小鼠体内表达溶菌酶的Paneth细胞减少；b) HUR直接与编码自噬蛋白ATG16L1和ATG7的mRNAs结合；以及c) HUR缺陷的肠上皮细胞自噬障碍与肠道微生物区系有关 生物失调和粘膜对损伤的易感性增加。基于这些令人兴奋的 观察，我们假设HUR控制着动态平衡和易感性 通过改变自噬活性来保护肠上皮细胞。提出了三个具体目标来 检验这一假设。1)确定HUR在调节自噬激活中的确切作用 2)研究HUR调控表达的机制 自噬基因ATGs；以及3)描述缺陷自噬在人类中的影响。 缺乏上皮对宿主-微生物的相互作用和粘膜对损伤的易感性。 完成这些具体目标将在概念上取得重大进展，将RBP HUR控制了肠粘膜中的自噬，并将为 开发新的治疗方法以在不同的临床条件下保持肠上皮的完整性 条件；这是退伍军人群体中常见的健康问题。

Disrupted integrity of the intestinal epithelium occurs commonly in various pathologies such as inflammatory bowel disease (IBD) and in surgical intensive care patients supported with total parenteral nutrition (TPN), predisposing the mucosa to destructive inflammation and leading to bacterial translocation to the bloodstream. Since the exact mechanism that governs intestinal epithelium homeostasis remains obscure, effective therapies to preserve mucosal epithelial integrity in patients with chronic inflammation and acute critical illness are limited. Posttranscriptional events, particularly altered messenger ribonucleic acid (mRNA) turnover and translation, are major mechanisms by which mammalian cells control gene expression in response to various stresses. Control of mRNA stability and translation is predominantly governed by RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) including microRNAs and long ncRNAs. Hu-antigen R (HuR) is among the most prominent translation and turnover regulatory RBPs, and has recently emerged as a master regulator of the epithelial integrity in the intestine. Autophagy is a cellular degradation system for numerous unwanted cytoplasmic components and intracellular pathogens; and it is essential for cell, tissue, and organ homeostasis. The autophagy pathway is increasingly recognized as an important mechanism for regulating defense and homeostasis of the intestinal epithelium in response to pathophysiological processes. However, the exact role of HuR in the regulation of autophagy activation in the intestinal mucosa remains unknown and is the focus of the current proposal. Our preliminary results indicate that a) intestinal epithelial tissue-specific deletion of HuR disrupts autophagy and causes the reduction of lysozyme-expressing Paneth cells in mice; b) HuR directly binds to the mRNAs encoding autophagy proteins ATG16L1 and ATG7; and c) disrupted autophagy in the HuR-deficient intestinal epithelium associates with gut microbiota dysbiosis and an increased susceptibility of the mucosa to injury. Based on these exciting observations, we HYPOTHESIZE that HuR controls homeostasis and susceptibility of the intestinal epithelium to injury by altering autophagy activity. Three specific aims are proposed to test the hypothesis. 1) To define the exact role of HuR in the regulation of autophagy activation in the intestinal epithelium; 2) to investigate the mechanism by which HuR regulates expression of the autophagy genes Atgs; and 3) to delineate the impact of defective autophagy in the HuR- deficient epithelium on host-microbial interaction and susceptibility of the mucosa to injury. Completion of these specific aims will make a significant conceptual advance by linking the RBP HuR with control of autophagy in the intestinal mucosa, and will create a fundamental basis for developing novel therapies to maintain intestinal epithelial integrity under various clinical conditions; which are common health problems in the Veteran population.