# Surgical Studies of Gut Permeability

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $559,576

## Abstract

Abstract
The protective intestinal mucosal barrier is a specialized domain responding to and
interacting with different luminal noxious substances and the microbiome. Acute gut
barrier dysfunction occurs commonly in patients with critical surgical disorders such as
trauma, thermal injury, sepsis, shock, massive surgical operations, and ischemic
postconditioning. Gut barrier dysfunction leads to the translocation of luminal toxic
substances and bacteria to the blood stream and, in some instances, results in multiple
organ dysfunction syndrome (MODS) and death. Effective therapies to preserve gut
barrier integrity are limited, because of poorly understood mechanisms of acute gut
barrier dysfunction in various critical surgical conditions. Recently, intercellular crosstalk
directed by the secretion of extracellular vesicles (EVs) has been gaining increasing
attention. EVs released from many cell types, including intestinal epithelial cells (IECs),
can transfer a variety of bioactive molecules to neighboring or distant tissues and hence
play previously unrecognized functional roles. The goal of this competitive renewal
application is to determine the role and mechanism of EV noncoding RNAs (ncRNAs) in
the control of intestinal barrier function under critical surgical conditions by carrying out a
series of multi-disciplinary studies. Our preliminary data indicate that the small
noncoding vault RNASs (vtRNAs) are critical transcripts present in EVs released from
IECs, and that the levels of EV vtRNAs increase in patients with sepsis and mice
exposed to septic stress. Ectopically expressed vtRNAs decrease the levels of tight
junctions and disrupt the intestinal barrier function. Mice bearing a maternal deletion of
exon 1 in the H19 gene (H19-/-) exhibit induced autophagy and decreased release of
vtRNA-enriched EVs after septic stress. Building on these exciting observations, we
now propose the paradigm-shifting hypothesis that vtRNAs in EVs secreted by IECs in
response to critical surgical stress play an important role in the pathogenesis of acute
gut barrier dysfunction, and that EV release from IECs is tightly regulated by long ncRNA
H19 and RNA-binding protein HuR via autophagy. Three specific aims are proposed to
test the hypothesis: 1) to define the roles of the vtRNA cargo of EVs generated from
human enterocytes in the regulation of intestinal barrier function during critical surgical
stress; 2) to identify novel targets of EV vtRNAs that play an important role in triggering
intestinal epithelial barrier dysfunction in response to critical surgical stress; and 3) to
test if H19 and HuR regulate the formation of vtRNA-rich EVs in IECs by altering
autophagy. Completion of these specific aims will uncover novel mechanisms
underlying the pathogenesis of acute gut barrier dysfunction in patients with critical
surgical disorders. It will also shed information needed to develop new biomarkers for
deteriorating acute gut barrier dysfunction and/or MODS an...

## Key facts

- **NIH application ID:** 10450157
- **Project number:** 5R01DK068491-16
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Jian-Ying Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $559,576
- **Award type:** 5
- **Project period:** 2004-08-25 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450157

## Citation

> US National Institutes of Health, RePORTER application 10450157, Surgical Studies of Gut Permeability (5R01DK068491-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10450157. Licensed CC0.

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