# Identifying Defects in the ENS Connectome of Hirschsprung Disease Models

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $29,555

## Abstract

PROJECT SUMMARY
Hirschsprung’s disease (HSCR) is a birth defect caused by a number of gene mutations, resulting in distal colon
that lacks an enteric nervous system (ENS). Children with HSCR are often treated by surgery to remove the
distal bowel where the ENS is missing (called ‘aganglionic bowel’), with the hope that the remaining ENS-
innervated colon will exhibit normal function. However, after surgery up to 50% of children with HSCR have
ongoing problems that are thought to be due to defects in the ENS-innervated colon. Numerous studies have
identified disproportionate increases in the number of inhibitory enteric neurons in proximal, ganglion cell-
containing colon tissue from HSCR patients and HSCR mouse models, raising the possibility that an imbalance
in inhibitory/excitatory neurotransmission may be the underlying cause of continued bowel dysmotility after
surgery. In order to improve colon dysmotility in HSCR, we first need a better understanding of the contributions
of specific subtypes of myenteric neurons and ICC to colon motility patterns, and then identify which ENS/ICC
circuits are altered in HSCR. Our lab has employed newly developed optogenetic tools combined with a
technically innovative ex vivo preparation that keeps intrinsic and extrinsic ENS circuits intact, and we have
generated preliminary data describing these circuits and the distinct patterns of contractility they produce in the
adult mouse colon. For this proposal, I will use these techniques in two well-established mouse models of HSCR
(piebald lethal and Ret+/-) to test the hypothesis that disruption in inhibitory and excitatory circuits in the proximal
colon leads to abnormal colon motility behavior. In Aim 1, I will identify alterations in synaptic connectivity in
intrinsic ENS/ICC circuits due to HSCR-associated mutations, reveal which subtypes of myenteric neurons are
most affected, and directly correlate these changes to altered patterns of contractility. Aim 2 will determine
whether extrinsic parasympathetic input to ENS/ICC circuits and resulting contractile responses are abnormal in
HSCR mouse models. Finally, in Aim 3, I will optogenetically stimulate (using the light-activated ion channel,
channelrhodopsin, ChR2) excitatory and inhibitory enteric neurons to determine the effects of manipulating
excitatory/inhibitory tone on motility patterns in HSCR mouse models. Overall, the proposed experiments will
identify specific ENS/ICC circuit defects that produce dysmotility in mouse models of HSCR and determine
whether neuromodulation of the ENS-innervated colon, using external electrical or optogenetic stimulation, is
capable of correcting circuit defects to normalize bowel function.

## Key facts

- **NIH application ID:** 10109112
- **Project number:** 5F32DK120115-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kristen Michelle Smith-Edwards
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $29,555
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109112

## Citation

> US National Institutes of Health, RePORTER application 10109112, Identifying Defects in the ENS Connectome of Hirschsprung Disease Models (5F32DK120115-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10109112. Licensed CC0.

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