# Conserved mechanisms in epithelial niche regulation of intestinal stem cells

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $391,725

## Abstract

Project Summary
The goal of this proposal is to dissect the underlying mechanism of the Tao and TAOK
subfamily of Ste20 kinases in mediating mechanosensing and tissue growth in both Drosophila
and mouse intestines. Billions of cells in the human gastrointestinal (GI) tract epithelium are
shed and replaced every day. This fast pace of cell replacement also allows the intestine to
afford adaptive growth, during which the epithelium can expand or shrink rapidly according to
the need. Mechanistic study of tissue homeostasis in the human GI tract epithelium is, however,
rather difficult because of the complexity of cell types, pathways and microbes involved. The
Drosophila midgut has a similar but yet simpler anatomy and physiology than mammalian
intestines. With highly cell-specific markers and sophisticated genetic techniques available, as
well as a short life cycle to allow multiple generations of in vivo experiments, the Drosophila
midgut has become a highly valuable system to study complex intestinal biology. We have
recently discovered a novel function of the Drosophila Ste20 kinase Misshapen that mediates
food particle ingestion caused mechanical stretching signal to regulate growth. Another Ste20
kinase Tao functions upstream, and may link the membrane mechanosensing components to
Misshapen and downstream growth signaling. This pathway is well-conserved in mammals, with
homologs of Misshapen (MINK1, MAP4K4, and TNIK), as well as other Ste20 kinases including
Hippo (MST1 andMST2), can similarly interact with the downstream components LATS and
YAP. The functional analysis of these mammalian homologs, however, post a strong barrier due
to the high level of overlapping functions. Therefore, the complementary study of Tao in
Drosophila midgut and TAOK1/2 in mouse intestine will provide a better understanding of how
this conserved pathway mediate mechanosensing to affect intestinal tissue growth. This model
has physiological relevance, because human patients recovering from bowel resection, bariatric
surgery or radiation therapy have better intestinal growth after solid food intake. Meanwhile,
total parenteral nutrition, that is through intravenous supply only, causes intestinal mucosal
atrophy. Therefore, interaction between solid food and intestinal epithelium is beneficial, but the
mechanism is not well-understood. The genetic studies in Drosophila midgut and in mouse
intestine, followed by molecular and protein-protein interaction analyses will unveil their
sequence of action of this Tao pathway in transducing mechanical signals for adaptive growth
and should provide important insights into similar processes in human intestines.

## Key facts

- **NIH application ID:** 10817929
- **Project number:** 5R01DK083450-13
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Y. Tony Ip
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $391,725
- **Award type:** 5
- **Project period:** 2010-05-17 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817929

## Citation

> US National Institutes of Health, RePORTER application 10817929, Conserved mechanisms in epithelial niche regulation of intestinal stem cells (5R01DK083450-13). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10817929. Licensed CC0.

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