# Modulation of Reserve Stem Cells in Regeneration of Ischemic-injured Intestine

> **NIH NIH R03** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2020 · $114,000

## Abstract

Project Summary/Abstract
Intestinal transplantation is the only cure for patients suffering from intestinal failure that can no longer be
maintained on total parenteral nutrition and is the only treatment that re-establishes a patient's capacity to
receive oral nutrition. Despite a highly concerning level of graft failure, limited research has been conducted on
mechanisms to prevent intestinal injury and failure associated with transplantation. A key contributor to
allograft failure is intestinal ischemia-reperfusion (IR). In serial surgical biopsies from clinical cases with graft
failure, epithelial loss extends into the crypt base, similar to observations in animal models of IR. Within the
crypt exist two intestinal stem cell (ISC) populations critical to epithelial repair: a) Active ISC (aISC; highly
proliferative; Lgr5+; sensitive to injury) and b) reserve ISC (rISC; less proliferative; marked by Hopx; resistant to
injury). Preliminary, K01 derived data, demonstrates that following prolonged ischemic injury: 1. aISC undergo
apoptosis, 2. rISC (HOPX+) are preserved, 3. high levels of Hopx expression correlate with inhibition of spheroid
proliferation, and 4. decreased Hopx expression correlates with a `release' of spheroids to proliferate. Taken
together, these data indicate that Hopx+ cells are resistant to injury, and that Hopx may operate as a `molecular
switch' to control cellular proliferation. Interestingly, although Hopx expression has been exclusively used in the ISC
field as a biomarker to identify rISC, strong evidence exists in cancer biology that Hopx plays a functional role as a
regulator of cellular proliferation. What has not been investigated is if changes in Hopx expression in rISC modulate
cellular quiescence or activation to preserve ISC during IR injury and release ISC to proliferate during regeneration.
Therefore, this proposal will investigate the hypothesis that high levels of Hopx gene expression in rISC confer
resistance to IR injury by prohibiting cellular proliferation and that a decrease in Hopx expression in rISC during
repair allows those cells to become more proliferative and contribute to repair. The hypothesis will be tested by
two specific aims: (1) Determine the role Hopx+ cells play in epithelial regeneration following severe IR injury;
and (2) Determine the role Hopx expression plays in modulating rISC proliferation during and following I/R injury. To
accomplish specific aim 1, transgenic mouse models will be used to assess cellular mechanisms that regulate rISC
resistance to ischemic injury and determine Hopx+ rISC fate. In Aim 2, the in vivo porcine mesenteric vascular
occlusion model, utilized in the K01, will be used to evaluate the impact of Hopx expression changes on ISC
growth patterns and proliferation. The successful outcome of this project will determine if the Hopx cellular
pathway confers rISC resistance to ischemic injury and plays a role in rISC mediated regeneration following IR
injury which ...

## Key facts

- **NIH application ID:** 9839690
- **Project number:** 5R03OD026598-02
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** Liara M Gonzalez
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $114,000
- **Award type:** 5
- **Project period:** 2019-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839690

## Citation

> US National Institutes of Health, RePORTER application 9839690, Modulation of Reserve Stem Cells in Regeneration of Ischemic-injured Intestine (5R03OD026598-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9839690. Licensed CC0.

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