# Physical Signaling Mechanisms That Regulate Intestinal Architecture

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $417,988

## Abstract

PROJECT SUMMARY
Physical signals are increasingly recognized as playing an important role in modulating cell behavior. The
goal of this proposal is to characterize the cellular response to force-mediated signaling in the intestine and
esophagus using zebrafish and mouse models. We have shown that an activating mutation in smooth
muscle myosin heavy chain gene myh11 disrupts intestinal architecture in zebrafish meltdown mutants.
Physical signals arising from the mutant myosin activate a conserved redox signaling pathway in the
intestinal epithelium that drives the formation of plasma membrane protrusions known as invadopodia that
degrade matrix proteins. The invadopodia drive the invasive transformation and cystic expansion of the
epithelium. Animals that are heterozygous for the meltdown mutation develop normally but are sensitized to
form the homozygous cell invasion phenotype when oncogenic signaling pathways activated. The proposal
consists of three aims designed to understand how physical signals from unregulated myosin are processed
by digestive epithelia and how they may be risk factors for digestive disease.
The goal of the first aim are to understand how the mutant smooth muscle myosin initiates invadopodia in
the epithelium of meltdown mutants and to compare this to mechanisms that regulate invadopodia formation
in mammalian cells. Invadopodia have rarely if ever been observed in vivo, thus this aim offers the
opportunity to understand their regulation in a live animal model. The goal of the second aim is to
understand how co- activation of KRas and Wnt signaling sensitize heterozygous mutants to invasive
triggers. The experiments proposed for this aim have both basic and clinical relevance, as both pathways
are activated in human digestive cancers. The goal of the third aim is to characterize a recently engineered
mouse model of the meltdown mutation. This includes characterization of esophageal and intestinal
phenotypes in homozygous mutants, and comparison with mice newly engineered to carry knock-in
mutations that are identical to human MYH11 mutations associated with heritable motility syndromes.
Collectively, the proposed experiments will define novel factors and signaling mechanisms that establish and
maintain digestive organ architecture and function.

## Key facts

- **NIH application ID:** 10167702
- **Project number:** 5R01DK117124-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MICHAEL A PACK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,988
- **Award type:** 5
- **Project period:** 2020-05-19 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167702

## Citation

> US National Institutes of Health, RePORTER application 10167702, Physical Signaling Mechanisms That Regulate Intestinal Architecture (5R01DK117124-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10167702. Licensed CC0.

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