# Investigating the role of biomechanical forces on the enteric nervous system in Hirschsprung disease

> **NIH NIH K08** · UNIVERSITY OF VIRGINIA · 2024 · $165,456

## Abstract

PROJECT SUMMARY
As a pediatric surgeon at Texas Children’s Hospital, the nation’s largest children’s hospital and a central hub for
the treatment of Hirschsprung’s disease (HSCR)—a disorder caused by defective enteric nervous system (ENS)
development, I strive not only to deliver excellent surgical care, but also to decipher the mechanisms behind
disease etiology. In my practice, I remove the abnormal, aganglionic intestine and pull-through “normal”
ganglionated intestine but continue to be perplexed by the nearly 50% incidence of postoperative bowel
dysfunction. Thus, my goal as an aspiring surgeon-scientist is to investigate the postnatal mechanisms that result
in these poor postoperative outcomes. The K08 program is an ideal foundation to develop the technical and
scientific skills I need to make translational impact for my patients. The present application lays out a five-year
educational and research plan focused on identifying drivers of persistent postoperative dysfunction in the
ganglionated HSCR colon microenvironment. Enteric neurons have long been recognized as mechanically
sensitive to extrinsic force (axial stretch and radial distention) and intrinsic mechanics (tissue stiffness), both of
which are present before and after HSCR surgery. It is not known how these forces affect ENS phenotype and
function, which raises the question of whether known mechanosensitive ion channels and/or focal adhesion
kinase (FAK) signaling could be pathophysiological mediators of ENS responses to tension. Consistent with our
logic, the ion channel Piezo1 and focal adhesion molecule FAK are ubiquitously present in the gastrointestinal
tract, but their role in ENS response to biomechanical forces requires further investigation. My data demonstrates
that HSCR intestine at baseline has a dysregulated ECM, which leads to changes in tissue stiffness, and that
extrinsic force further dysregulates the ECM. Still, it remains unclear how these changes in the ECM
microenvironment regulate the ENS. Therefore, we hypothesize that biomechanical forces on the intestine have
Piezo1-FAK dependent effects on the ENS and regulate ECM composition in a manner that governs the ENS
microenvironment, which ultimately contributes to gut dysfunction in HSCR. I will address this research question
in two aims, under the guidance of my mentor, Dr. Keswani, and expert scientific advisory committee. In Aim 1,
I will define the role of clinically relevant, extrinsic mechanical forces on the ENS in normal and HSCR intestine.
This will allow me to develop new technical expertise in live cell calcium imaging, ex vivo tissue culture, and in
vivo tension models to evaluate the signaling of Piezo1-FAK in ENS responses to extrinsic mechanical forces.
Aim 2 will focus on testing how biomechanical forces regulate the ECM to alter the ENS microenvironment in
HSCR, and whether changes in the ECM are indicative of post-surgical prognosis in HSCR. In this aim, I will
work with novel biomechanical a...

## Key facts

- **NIH application ID:** 10897149
- **Project number:** 5K08DK133673-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Lily S Cheng
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $165,456
- **Award type:** 5
- **Project period:** 2022-09-30 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897149

## Citation

> US National Institutes of Health, RePORTER application 10897149, Investigating the role of biomechanical forces on the enteric nervous system in Hirschsprung disease (5K08DK133673-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10897149. Licensed CC0.

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