Posttranscriptional Control of Gut Mucosal Defense and Homeostasis

肠道粘膜防御和稳态的转录后控制

• 批准号: 10265340
• 负责人: Jian-Ying Wang
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265340
• 关键词: 3' Untranslated Regions; Acute; Affect; Area; Autophagocytosis; Bacterial Translocation; Binding; Blood Circulation; Cell membrane; Cells; Chronic; Clinical; Colon; Critical Illness; Data; Defense Mechanisms; Disease; Elements; Environment; Epithelial; Epithelial Cells; Event; Functional disorder; Funding; Gene Expression; Genes; Goals; Growth; Gut Mucosa; H19 gene; Health; Homeostasis; HuR protein; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intestinal Mucosa; Intestines; Knowledge; Link; Lysosomes; Mammalian Cell; Mediating; MicroRNAs; Mucous Membrane; Muramidase; Mus; Operative Surgical Procedures; Organ; Paneth Cells; Pathologic; Pathology; Pathway interactions; Patient Care; Patients; Permeability; Play; Polyamines; Post-Transcriptional Regulation; Predisposition; Process; Proteins; RNA; RNA-Binding Proteins; Regulation; Regulator Genes; Reporting; Role; STIM1 gene; Signal Transduction; Small intestine mucous membrane; Sodium Dextran Sulfate; Stress; Surgical Intensive Care; System; Testing; Tight Junctions; Tissues; Total Parenteral Nutrition; Trans-Activators; Transcript; Translations; Untranslated RNA; Untranslated Regions; Vacuole; WNT Signaling Pathway; base; dysbiosis; effective therapy; experimental study; gastrointestinal epithelium; gut microbiota; host-microbe interactions; intestinal epithelium; intestinal homeostasis; microbiota; migration; military veteran; novel therapeutics; pathogen; preservation; prevent; programs; response; restoration; therapeutically effective

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.

肠上皮完整性的破坏通常发生在各种病理中 例如炎性肠病（IBD）和在外科重症监护患者中， 全胃肠外营养（TPN），易使粘膜发生破坏性炎症， 细菌转移到血液中。因为控制肠道的确切机制 上皮内稳态仍然不清楚，有效的治疗方法，以保护粘膜上皮 慢性炎症和急性危重病患者的完整性有限。 转录后事件，特别是改变信使核糖核酸（mRNA）的周转， 翻译是哺乳动物细胞控制基因表达的主要机制， 应对各种压力。mRNA稳定性和翻译的控制主要是 由RNA结合蛋白（RBP）和非编码RNA（ncRNA）（包括microRNA）控制 和长的ncRNA。Hu-antigen R（HuR）是最重要的翻译和周转蛋白之一， 调节性RBP，并且最近已经出现作为上皮完整性的主调节剂， 肠。自噬是一种细胞降解系统， 成分和细胞内病原体;它是细胞，组织和器官所必需的 体内平衡自噬途径越来越被认为是一种重要的机制， 调节肠上皮细胞的防御和稳态， 病理生理过程然而，HuR在自噬调节中的确切作用 肠粘膜中的活化仍然是未知的，并且是当前提议的焦点。 我们的初步结果表明：a）肠上皮组织特异性HuR缺失 破坏自噬并导致小鼠中表达溶菌酶的潘氏细胞减少; B） HuR直接与编码自噬蛋白ATG 16 L1和ATG 7的mRNA结合;以及 HuR缺陷型肠上皮细胞中的自噬破坏与肠道微生物群相关 生态失调和粘膜对损伤的敏感性增加。基于这些令人兴奋的 观察，我们假设，HuR控制稳态和易感性， 肠上皮细胞通过改变自噬活性而损伤。提出了三个具体目标， 测试假设。1)明确HuR在自噬激活调控中的确切作用 2）探讨HuR调控表达的机制 自噬基因Atgs;和3）描绘缺陷性自噬在HuR中的影响， 缺乏上皮对宿主-微生物相互作用和粘膜对损伤的敏感性的影响。 这些具体目标的完成将通过将不丹王家警察与不丹王家警察联系起来，在概念上取得重大进展。 HuR具有控制肠粘膜自噬的作用，并将为 开发新的疗法以在各种临床条件下维持肠上皮完整性 条件;这是退伍军人中常见的健康问题。