# Surgical Studies on Mucosal Homeostasis

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2022 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10456028
- **Project number:** 5I01BX000713-10
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Rao N. Jaladanki
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2010-10-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456028

## Citation

> US National Institutes of Health, RePORTER application 10456028, Surgical Studies on Mucosal Homeostasis (5I01BX000713-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10456028. Licensed CC0.

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