Surgical Studies on Mucosal Homeostasis

粘膜稳态的外科研究

• 批准号: 9889594
• 负责人: Rao N. Jaladanki
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889594
• 关键词: Acute; Affect; Aging; Anabolism; Apoptosis; Area; Bacteria; Binding Proteins; Blood; Burn injury; Cause of Death; Cell physiology; Critical Illness; Development; Disease; Epithelial; Epithelial Cells; Epithelium; Exhibits; Functional disorder; Funding; Gene Expression; Genes; Genetic Transcription; Goals; Gut Mucosa; H19 gene; Hemorrhage; Homeostasis; HuR protein; IGF2 gene; Impairment; Inflammation; Injury; Intestinal Mucosa; Intestines; Link; Maintenance; Messenger RNA; MicroRNAs; Mission; Molecular; Morbidity - disease rate; Mucous Membrane; Multiple Organ Failure; Mus; Natural regeneration; Nucleotides; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Permeability; Play; Polyamines; Population; Process; Protein phosphatase; Proteins; RNA; RNA-Binding Proteins; Regulator Genes; Role; STIM1 gene; Sepsis; Shock; Stream; Stress; Testing; Time; Tissue Differentiation; Tissues; Toxin; Transfection; Translations; Trauma; Traumatic injury; Untranslated RNA; base; cIAP1 protein; cell motility; cell type; chromatin remodeling; effective therapy; experimental study; gastrointestinal epithelium; healing; heat injury; human disease; intestinal epithelium; intestinal homeostasis; intestinal maturation; mRNA Stability; miRNA expression profiling; migration; mortality; novel; novel therapeutics; operation; preservation; prevent; programs; protein metabolism; receptor; repaired; response; restoration; wound

Patients with critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations are commonly complicated with acute gut mucosal injury and bleeding. Disruption of the gut epithelial integrity causes sepsis and in some instances acts as the trigger that drives multiple organ dysfunction syndrome (MODS), a leading cause of death in critically ill patients. Effective therapies to enhance mucosal defense and promote epithelial repair after acute injury in patients with critical surgical illnesses are limited, contributing to massive mucosal hemorrhage, impaired repair, and gut barrier dysfunction. During the previous funding periods, we have demonstrated that protein phosphatase 2A (PP2A)-associated protein α4 plays an important role in intestinal mucosal regeneration and defense, but its exact mechanism underlying α4-regulated intestinal homeostasis remains largely unknown. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long ncRNAs (lncRNAs), have recently emerged as a novel class of master regulators of the intestinal epithelium homeostasis and are also implicated in different human diseases. miRNAs and lncRNAs modulate expression of target genes and thus regulate a variety of cellular processes. Our preliminary results indicate that a) targeted deletion of α4 in mice decreased the levels of mucosal miR-503 and lncRNA uc.230 in the intestine; b) specific inhibition of miR-503 and uc.230 by transfection with their antagonisms repressed intestinal epithelial repair after wounding and also enhanced epithelial cell apoptosis; and c) miR-503 inhibited expression of antizyme (AZ; a negative regulator of polyamine biosynthesis), whereas uc.230 up-regulated Rac1 and inhibitor of apoptosis protein 1 (IAP1). Based on these exciting observations, we HYPOTHESIZE that α4 promotes intestinal epithelial homeostasis by modulating miRNA miR- 503 and lncRNA uc.230 in critical surgical conditions. Three specific aims are proposed to test the hypothesis: 1) to examine the expression profiles of miRNAs and lncRNAs in the α4-deficient intestinal epithelium in response to surgical stress; 2) to determine the exact roles of miR-503 and uc.230 in α4-regulated mucosal repair and apoptosis; and 3) to define the mechanisms by which miR-503 and uc.230 regulate expression of AZ, Rac1, and IAP1. Completion of these specific aims will make a conceptual advance by linking α4/ncRNA pathway with gut epithelium homeostasis under critical surgical conditions. These studies will also create a fundamental basis for development of novel therapies to preserve epithelial integrity in our VA patients, thus decreasing morbidity and mortality of massive mucosal injury and inflammation, delayed repair, sepsis, and MODS by targeting α4 and its regulatory ncRNAs.

患有严重外科疾病的患者，例如创伤、热损伤、休克、败血症和 大型外科手术常并发急性肠粘膜损伤， 肠道上皮完整性的破坏会导致败血症，并且在某些情况下会导致败血症。 导致多器官功能障碍综合征 (MODS) 的触发因素，MODS 是导致死亡的主要原因 增强粘膜防御和促进上皮细胞的有效治疗。 患有严重外科疾病的患者急性损伤后的修复有限，导致 之前出现大量粘膜出血、修复受损和肠道屏障功能障碍。 资助期间，我们已经证明蛋白磷酸酶 2A (PP2A) 相关蛋白 α4在肠粘膜再生和防御中发挥重要作用，但其确切作用 α4 调节肠道稳态的机制仍然很大程度上未知。 非编码 RNA (ncRNA)，包括 microRNA (miRNA) 和长 ncRNA (lncRNA)， 最近出现的一类新型的肠上皮稳态主要调节因子 并且还与不同的人类疾病有关。 靶基因的表达，从而调节多种细胞过程。 我们的初步结果表明，a) 小鼠体内 α4 的靶向缺失降低了 b) 肠道中粘膜miR-503和lncRNA uc.230；b) miR-503和的特异性抑制； uc.230通过转染后以其拮抗作用抑制肠上皮修复 损伤并增强上皮细胞凋亡；c) miR-503 抑制 抗酶（AZ；多胺生物合成的负调节因子），而 uc.230 上调 Rac1 和凋亡蛋白抑制剂 1 (IAP1) 基于这些令人兴奋的观察结果，我们。 假设 α4 通过调节 miRNA miR- 促进肠上皮稳态 危重手术条件下的 503 和 lncRNA uc.230。 提出了三个具体目标来检验假设：1）检查 α4 缺陷肠上皮中的 miRNA 和 lncRNA 对手术应激的反应 2) 确定 miR-503 和 uc.230 在 α4 调节的粘膜修复中的确切作用 细胞凋亡；3) 定义 miR-503 和 uc.230 调节表达的机制 AZ、Rac1 和 IAP1 的完成将在概念上取得进展。 在关键手术条件下将 α4/ncRNA 通路与肠上皮稳态联系起来。 这些研究还将为开发新疗法奠定基础 保持 VA 患者的上皮完整性，从而降低 VA 患者的发病率和死亡率 通过靶向 α4 来治疗大规模粘膜损伤和炎症、延迟修复、败血症和 MODS 及其调控 ncRNA。