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.
Disrupted integrity of the intestinal epithelium occurs commonly in various pathologies such as inflammatory bowel disease, and in surgical intensive care patients supported with total parenteral nutrition. Effective therapies to preserve the epithelial integrity in patients with chronic inflammation and acute critical illness are limited to date, because of the lack of knowledge about the mechanism underlying the intestinal epithelium homeostasis. Efforts to identify the processes governing the intestinal epithelial defense and to developing effective therapeutics to maintain mucosal epithelial integrity in stressful environments are vitally important. Studies proposed here are to determine the role of RNA-binding protein HuR in the regulation of autophagy, a crucial innate defense mechanism in the intestinal mucosa. Completion of these experiments will provide supportive data to strengthen our long-term goal that is to develop more effective therapeutic approaches for gut mucosal injury/inflammation-associated diseases for our VA patients.
Showing the most recent 10 out of 21 publications
