# Mechanisms of tuft cell mediated regulation of the intestinal stem cell niche following injury

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $326,250

## Abstract

One of the major and devastating adverse effects of radiation therapy is the development of radiation enteritis
(RE). The number of patients receiving radiation therapy in the USA, as a component of their primary cancer
treatment, is forecast to increase by more than 20% over the next decade to almost 600,000 per year. RE is an
intestinal inflammatory process that occurs in response to radiotherapy. It is a major health concern
characterized by abdominal pain, diarrhea, and rectal bleeding. It can be complicated by translocation of gut
bacteria into the circulation due to the loss of intestinal epithelial cells, disruption of intraepithelial tight junctions,
and loss of regenerative ability resulting in impairment of gut function and even death. Relatively little is known
about the mechanisms underlying the intestinal epithelial injury repair, stem cell survival and crypt regeneration
in RE. Doublecortin like kinase 1 (Dclk1) marks intestinal tuft cells and deletion of Dclk1 within intestinal
epithelial cells resulted in premature death of mice following severe radiation injury, suggesting that Dclk1 is a
major mediator of the crypt epithelial response to genotoxic injury. We reported that Dclk1 interacts with ataxia-
telangiectasia mutated (ATM) and phosphorylates ATM activating the DNA damage response (DDR) following
radiation injury . Furthermore, intestinal epithelial cells overexpressing Dclk1 are more resistant to radiation than
the control cells. These data suggest that Dclk1+ tuft cell plays a critical role in epithelial cell survival following
severe genotoxic injury. Recently, single cell analysis in the intestine has revealed that Dclk1+ epithelial tuft cell
is the primary source of Cox1 (Ptgs1) and Cox2 (Ptgs2). Based on our previous studies, Cox1 and Cox2 are the
major source of PGE2 in the intestine, that protects the gut after severe radiation injury. However, the molecular
mechanism that regulates the survival of intestinal tuft cells following severe injury is unclear and the role of
intestinal crypt tuft cells in epithelial stem cell survival is completely unknown. Our central hypothesis is that
intestinal crypt tuft cell survival following severe genotoxic injury is mediated by Dclk1-dependent
regulation of the ATM/ATR DNA damage response; further these crypt tuft cells coordinate the survival
of neighboring epithelial stem cells via a PGE2-dependent mechanism. We will test our hypothesis with the
following specific aims: Aim 1: To elucidate the molecular mechanism by which tuft cells survive lethal
dose radiation injury. Aim 2: To determine the mechanisms by which tuft cells coordinate the survival of
crypt intestinal stem cells (ISCs). Aim 3: To determine the role of tuft cell specific PGE2 on intestinal
crypt regeneration and epithelial restitution following severe radiation injury.
The proposed study will (1) determine the mechanisms by which surviving intestinal epithelial Dclk1+ tuft
following severe genotoxic injury coor...

## Key facts

- **NIH application ID:** 9997912
- **Project number:** 5R01DK119495-02
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Courtney Wayne Houchen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,250
- **Award type:** 5
- **Project period:** 2019-08-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997912

## Citation

> US National Institutes of Health, RePORTER application 9997912, Mechanisms of tuft cell mediated regulation of the intestinal stem cell niche following injury (5R01DK119495-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997912. Licensed CC0.

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