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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000332-10
Application #
9840825
Study Section
Special Emphasis Panel (ZRD1)
Project Start
2009-04-01
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Baltimore VA Medical Center
Department
Type
DUNS #
796532609
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Xiao, Lan; Wu, Jing; Wang, Jun-Yao et al. (2018) Long Noncoding RNA uc.173 Promotes Renewal of the Intestinal Mucosa by Inducing Degradation of MicroRNA 195. Gastroenterology 154:599-611
Lai, Keane K Y; Kweon, Soo-Mi; Chi, Feng et al. (2017) Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6. Gastroenterology 152:1477-1491
Wang, Peng-Yuan; Wang, Shelley R; Xiao, Lan et al. (2017) c-Jun enhances intestinal epithelial restitution after wounding by increasing phospholipase C-?1 transcription. Am J Physiol Cell Physiol 312:C367-C375
Zhang, Yuan; Zhang, Yun; Xiao, Lan et al. (2017) Cooperative Repression of Insulin-Like Growth Factor Type 2 Receptor Translation by MicroRNA 195 and RNA-Binding Protein CUGBP1. Mol Cell Biol 37:
Liu, Lan; Zhuang, Ran; Xiao, Lan et al. (2017) HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation. Mol Cell Biol 37:
Gu, Hui; Yu, Jingwen; Dong, Daoyin et al. (2016) High Glucose-Repressed CITED2 Expression Through miR-200b Triggers the Unfolded Protein Response and Endoplasmic Reticulum Stress. Diabetes 65:149-63
Hansraj, Natasha Z; Xiao, Lan; Wu, Jing et al. (2016) Posttranscriptional regulation of 14-3-3? by RNA-binding protein HuR modulating intestinal epithelial restitution after wounding. Physiol Rep 4:
Phatak, P; Byrnes, K A; Mansour, D et al. (2016) Overexpression of miR-214-3p in esophageal squamous cancer cells enhances sensitivity to cisplatin by targeting survivin directly and indirectly through CUG-BP1. Oncogene 35:2087-97
Xiao, Lan; Rao, Jaladanki N; Cao, Shan et al. (2016) Long noncoding RNA SPRY4-IT1 regulates intestinal epithelial barrier function by modulating the expression levels of tight junction proteins. Mol Biol Cell 27:617-26
Li, Yanwu; Chen, Gang; Wang, Jun-Yao et al. (2016) Post-transcriptional regulation of Wnt co-receptor LRP6 and RNA-binding protein HuR by miR-29b in intestinal epithelial cells. Biochem J 473:1641-9

Showing the most recent 10 out of 21 publications