Mucosal Repair in Gut Surgical Disorders

肠道外科疾病的粘膜修复

• 批准号: 9274248
• 负责人: Jian-Ying Wang
• 金额: $ 27.41万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274248
• 关键词: 3' Untranslated Regions; Acute; Apoptosis; Bacteria; Bacterial Translocation; Binding; Binding Proteins; Blood; CDK4 gene; Cause of Death; Cell Survival; Cellular Stress Response; Coculture Techniques; Critical Illness; Development; Disease; Duodenum; Elements; Epithelial; Epithelial Cells; Event; FOS gene; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Hemorrhage; HuR protein; Impaired wound healing; Impairment; In Vitro; Injury; JUN gene; Link; Maintenance; Mammalian Cell; Mediating; Messenger RNA; MicroRNAs; Modeling; Modification; Molecular; Molecular Profiling; Morbidity - disease rate; Mucous Membrane; Multiple Organ Failure; Operative Surgical Procedures; Patients; Pattern; Play; Poison; Polyamines; Process; RNA-Binding Proteins; Regulation; Research; Role; Sepsis; Shock; Signal Transduction; Stomach; Stream; Stress; Testing; Time; Tissues; Transcription Factor AP-1; Translations; Trauma; Untranslated Regions; WNT Signaling Pathway; base; c-myc Genes; clinical application; drug development; effective therapy; experimental study; genome-wide; healing; heat injury; injury and repair; migration; mortality; novel; novel therapeutics; operation; overexpression; programs; public health relevance; receptor; repaired; response

DESCRIPTION (provided by applicant): Acute gut mucosal injury occurs commonly in various critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations. Since the exact mechanisms underlying mucosal injury and repair are still obscure, effective therapies to preserve the epithelial integrity in patients with critical surgical illnesss are limited, contributing to mucosal hemorrhage, delayed healing, epithelial barrier dysfunction, and the translocation of luminal toxic substances and bacteria to the blood stream. During previous funding period, we have demonstrated that activation of Wnt signaling stimulates mucosal healing after acute injury and also identified a novel mechanism through which the RNA-binding proteins HuR and AUF1 regulate expression of c-Myc and JunD in critical surgical conditions. Recently, the essential contribution of posttranscriptional events, particularly altere mRNA turnover and translation through microRNAs (miRNAs), in the control of gene expression program in the mucosal tissues is becoming increasingly recognized, but little is known about their importance in the control of mucosal injury/repair 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 miRNA-222 (miR-222) and miR-503 play an important role in the regulation of mucosal healing after acute injury in critical surgical conditions by altering the stability and/or translation of arget mRNAs. Three specific aims are proposed to test the hypothesis. 1) To define the exact roles of miR-222 and miR-503 in mucosal healing after acute injury in critical surgical conditions. 2) To determine if miR-222 and miR-503 regulate mucosal healing by altering the stability and translation of their target mRNAs. 3) To characterize the exact mechanism by which miR-222 and miR-503 regulate expression of key molecules of Wnt signals under surgical stress. Completion of these specific aims will make a significant conceptual advance by linking the miRNA- mediated posttranscriptional regulation with mucosal healing in patients with critical surgical illness and will create a fundamental base for development of novel therapies to preserve the epithelial integrity. Moreover, the identification of the mRNA targets that mediate the actions of miRNAs in mucosal healing will also reveal previously unrecognized components of cellular stress responses that may serve as targets for more traditional drug development.

描述（由申请人提供）：急性肠粘膜损伤通常发生在各种关键手术疾病中，例如创伤，热损伤，休克，败血症和大规模手术手术。由于粘膜损伤和修复的基本机制仍然晦涩难懂，因此保留严重手术疾病患者上皮完整性的有效疗法有限，有限，有助于粘膜出血，延迟愈合，上皮屏障功能障碍以及易位的易位性药物和细菌的易位。到血流。在以前的资金期间，我们已经证明，Wnt信号的激活在急性损伤后刺激粘膜愈合，并确定了一种新型机制，通过该机制，RNA结合蛋白HUR和AUF1在关键手术条件下调节C-Myc和Jund的表达。最近，转录后事件的基本贡献，尤其是改变mRNA周转和通过microRNA（miRNA）的翻译，在粘膜组织中基因表达程序的控制中越来越认识到，但对它们在控制粘膜损伤中的重要性知之甚少/在关键手术条件下修复。基于我们在先前的资金期间的重大进展和令人兴奋的初步研究，在此竞争性更新应用中提出的实验是测试miRNA-222（miR-222）（miR-222）和miR-503在调节粘膜愈合中起重要作用的假设在急性手术条件下急性损伤后，通过改变ARGET mRNA的稳定性和/或翻译。提出了三个特定目标来检验该假设。 1）在急性手术条件下，在急性损伤后定义了miR-222和miR-503在粘膜愈合中的确切作用。 2）确定miR-222和miR-503是否通过改变其靶标mRNA的稳定性和翻译来调节粘膜愈合。 3）表征miR-222和miR-503在手术应激下调节WNT信号的关键分子的表达的确切机制。这些特定目标的完成将通过将miRNA介导的转录后调节与患有严重手术疾病的患者的粘膜愈合联系起来，从而实现重大的概念进步，并将为开发新疗法的基本基础，以保持上皮完整性。此外，介导miRNA在粘膜愈合中的作用的mRNA靶标的鉴定还将揭示以前未被认可的细胞应激反应组成部分，这些组成部分可能是传统药物开发的靶标。