# Posttranscriptional Control of Gut Mucosal Defense and Homeostasis

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2020 · —

## Abstract

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 t...

## Key facts

- **NIH application ID:** 9840825
- **Project number:** 5I01BX000332-10
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Jian-Ying Wang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840825

## Citation

> US National Institutes of Health, RePORTER application 9840825, Posttranscriptional Control of Gut Mucosal Defense and Homeostasis (5I01BX000332-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840825. Licensed CC0.

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