# Regulation of Intestinal Epithelial Cell Proliferation

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $564,171

## Abstract

PROJECT SUMMARY
The intestinal epithelium possesses one of the highest self-renewing capacities among tissues due to the
presence and functions of active intestinal stem cells (aISCs). Concurrently, aISCs are susceptible to injury due
to various pathological conditions because of their high proliferative capability. Recent studies have shown that
subpopulations of intestinal epithelial cells such as reserve stem cells (e.g., those marked by Bmi1, Hopx1, Lrig1,
mTert), progenitors (Atoh1, Dll1), and several terminally differentiated cell types (enteroendocrine, Paneth,
enterocyte) become activated in the aftermath of injury to replenish the basal crypt compartment, which then
reconstitutes cell populations of the villi. Additionally, recent studies demonstrated that subpopulations of
mesenchymal cells marked by Pdgfra, Gli1, or Cd81 provide essential factors to sustain the renewal of the stem
cell niche. Nonetheless, there needs to be a complete understanding of the mechanisms that regulate
communication between various cell types and their influence on the regenerative capacity of the intestine.
Identifying the mechanisms that coordinate interactions between multiple cell populations (e.g., epithelial cells
and mesenchymal cells) in the intestine during regeneration may aid in identifying targets for therapeutic
interventions.
The Long-Term Goal of this research proposal is to elucidate the mechanisms regulating the activation of
and coordination between intestinal epithelial and stromal cells upon γ radiation-induced injury. Our
exciting preliminary results showed that Sonic Hedgehog (SHH), normally absent under homeostatic conditions,
increases in the intestinal epithelium shortly after irradiation. Furthermore, new preliminary results demonstrate
increased levels of HIF1α and KLF4 in the intestinal epithelium upon injury and their ability to induce Shh
promoter activity by direct binding to its promoter. SHH ligands then induce Gli1 expression in stromal cells and
stimulate their proliferation. In turn, activated stromal cells secrete WNT ligands, promoting the expansion of
Bmi1+ cells to repopulate the intestinal crypts. Inhibition of SHH and WNT signaling, in vitro and in vivo, abrogates
regeneration of the intestinal epithelium post-irradiation. Based on these compelling and exciting findings, our
Central Hypothesis is that precise spatiotemporal communication between intestinal epithelial and
stromal cells is fundamental for regenerating the intestinal epithelium following radiation injury. To test
this hypothesis, we designed three Specific Aims: (SA1) to investigate the mechanism that regulates the
induction of Sonic Hedgehog (SHH) signaling in intestinal epithelial cells upon irradiation; (SA2) to identify and
characterize the stromal cell population(s) promoting intestinal regeneration; and (SA3) to examine the
mechanism underlying the intestinal epithelial cell activation upon stromal stimulation. The proposed studies will
advance our...

## Key facts

- **NIH application ID:** 10978590
- **Project number:** 2R01DK052230-24A1
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Vincent W Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $564,171
- **Award type:** 2
- **Project period:** 1997-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978590

## Citation

> US National Institutes of Health, RePORTER application 10978590, Regulation of Intestinal Epithelial Cell Proliferation (2R01DK052230-24A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10978590. Licensed CC0.

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