Defective regulation of early intestinal mucosal restitution underlies various critical pathological states such as acute mucosal injury/hemorrhage, impaired repair of erosions/ulcers, disruption of epithelial integrity, and epithelial barrier dysfunction. Since the exact mechanisms of early rapid mucosal restitution after superficial wounds are still obscure, effective therapies to preserve gut epithelial integrity in clinic are limited, especially in patiets with critical surgical illnesses such as trauma and sepsis. The restoration of normal intestinal mucosal integrity after injury and/or ulceration requires epithelial cell decisions that regulate signaling networks controlling expression of various genes. Posttranscriptional events, particularly altered mRNA turnover and translation, are major mechanisms by which mammalian cells control gene expression in response to various stresses. Changes in mRNA stability and translation are predominantly governed by RNA-binding proteins (RBPs) and microRNAs (miRNAs) that are emerged as master regulators of maintenance of gut epithelial integrity. However, little is known about the roles of RBPs and miRNAs in the mechanisms underlying rapid mucosal restitution after acute injury. HuR is among the most prominent translation and turnover regulatory RBPs and is recently show to regulate cell motility. Our preliminary results indicate that a) HuR silencing represses intestinal epithelial cell (IEC) migration over the wounded area in an in vitro model; b) tissue specific HuR knockout inhibits early intestinal mucosal repair after injury; and c) miR-195 overexpression represses early epithelial repair in vitro, but this repression is rescued by increasing HuR levels. Based on these exciting observations, we HYPOTHESIZE that HuR is essential for intestinal epithelial restitution after injury by altering the stability and translation of target mRNAs encoding cell migration-regulatory proteins and its effect is regulated by given miRNAs.
Three specific aims are proposed to test the hypothesis. 1) To determine the exact role of HuR in early intestinal mucosal restitution after acute injury. 2) To define new target mRNAs of HuR and its role in the regulation of mRNA stability and translation in the intestinal epithelium after wounding. 3) To investigate the interactions between HuR and given miRNAs in the control of stability and translation of target mRNAs in response to epithelial injury. Completion of these specific aims will make a significant conceptual advance by linking HuR/miRNA-mediated posttranscriptional gene regulation with early mucosal restitution in the intestine and will create a fundamental base for development of new therapeutic approaches for gut mucosal injury-related diseases and for maintaining epithelial integrity under various clinical conditions.

Public Health Relevance

Early mucosal restitution is an important primary repair modality in the gastrointestinal (GI) trat and its defective regulation underlies various GI mucosal injury-associated disorders. These disorders occur commonly and are major health issues in our veteran population. However, the effective therapies for preventing gut mucosal injury and for enhancing mucosal repair in clinic are limited to date. Thus, improving the understanding of the process by which gut mucosa repairs itself rapidly after acute injury is the first step towards therapeutic initiatives in thisarea. Based on our long-term interest and exciting preliminary results, studies proposed here are to determine the roles and mechanisms of RNA-binding protein HuR and microRNAs in the regulation of GI mucosal restitution after acute injury. Completion of these experiments will provide supportive data to strengthen our long-term goal that is to develop more effective therapeutic approaches for GI mucosal injury-related diseases for our VA patients.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000332-08
Application #
9486822
Study Section
Gastroenterology (GAST)
Project Start
2009-04-01
Project End
2018-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
8
Fiscal Year
2018
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:
Xu, Yan; Chen, Jie; Xiao, Lan et al. (2016) Transcriptional regulation of importin-?1 by JunD modulates subcellular localization of RNA-binding protein HuR in intestinal epithelial cells. Am J Physiol Cell Physiol 311:C874-C883
Zou, Tongtong; Jaladanki, Suraj K; Liu, Lan et al. (2016) H19 Long Noncoding RNA Regulates Intestinal Epithelial Barrier Function via MicroRNA 675 by Interacting with RNA-Binding Protein HuR. Mol Cell Biol 36:1332-41
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

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