# Intestinal Mucosal Growth in Health and Surgical Diseases

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $561,268

## Abstract

Abstract
 Inhibition of intestinal mucosal growth occurs commonly in various critical surgical disorders, particularly
in patients who undergo massive gastrointestinal surgical resections and are then supported with total
parenteral nutrition (TPN). Disrupted mucosal renewal impairs gut barrier dysfunction and leads to sepsis
and, in some instances, multiple organ dysfunction syndrome and death. Effective therapies to preserve
the intestinal epithelial integrity in patients with critical surgical illnesses are limited, as the mechanisms
that regulate gut mucosal renewal in stressful environments are poorly understood. With on-going support
for this project, our group was the first to implicate RNA-binding proteins (RBPs) and long noncoding RNAs
(lncRNAs) in gut mucosal growth and to show that dysregulation of RBP HuR and lncRNA uc.173 impairs
epithelial renewal, compromises epithelial host defenses, and disrupts the intestinal barrier. However, it
remains unknown how dysregulated HuR and uc.173 affect growth of the intestinal mucosa and how these
findings can be exploited to benefit patients with critical surgical illnesses. Rapid self-renewal of the
intestinal mucosa is driven by intestinal stem cells (ISCs) located at the crypt base. Paneth cells (PCs)
constitute the niche for ISCs in the small intestine and provide multiple secreted (WNT, EGF) and surfaced-
bound (Notch ligand) niche signals essential for ISC maintenance and function. Mitochondrial homeostasis
is essential for sustaining the PC/ISC niche, whereas disrupted mitochondrial function leads to PC defects
and ileitis. Our preliminary studies indicate that defects in PCs induced by targeted HuR deletion or uc.173
silencing resulted in the concomitant loss of ISC activity in vivo as well as ex vivo and that HuR knockout
and uc.173 inhibition also caused mitochondrial dysfunction, along with reduced levels of WNT3 and Notch
ligands in PCs. Building on these exciting observations, we now propose the paradigm-shifting hypothesis
that HuR and uc.173 regulate the PC/ISC niche by maintaining mitochondrial homeostasis, in turn
regulating intestinal mucosal renewal and adaptation in critical surgical diseases. Two specific aims are
proposed to test the hypothesis: 1) to define the exact role of the PC/ISC niche in HuR/uc.173-regulated
intestinal mucosal growth under critical surgical conditions; and 2) to determine if HuR and uc.173 regulate
PC/ISC niche function by modulating mitochondrial metabolism in response to critical surgical stress.
Completion of these specific aims will uncover novel mechanisms underlying the pathogenesis of intestinal
mucosal growth inhibition in patients with critical surgical disorders. It will also establish a fundamental
basis for developing new effective therapeutics to promote gut mucosal growth/adaptation by targeting the
PC/ISC niche activity via HuR and uc.173.

## Key facts

- **NIH application ID:** 10907693
- **Project number:** 5R01DK057819-21
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Jian-Ying Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $561,268
- **Award type:** 5
- **Project period:** 2000-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907693

## Citation

> US National Institutes of Health, RePORTER application 10907693, Intestinal Mucosal Growth in Health and Surgical Diseases (5R01DK057819-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10907693. Licensed CC0.

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