# Characterizing neurogenic progenitors in the adult intestine

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $363,312

## Abstract

Project Summary
The enteric nervous system (ENS) is of fundamental importance to human health through its regulation of all
aspects of gastrointestinal (GI) function, most notably gut motility. Congenital or acquired abnormalities of the
ENS consequently can lead to serious functional GI disorders, including esophageal achalasia, gastroparesis,
intestinal pseudo-obstruction, irritable bowel syndrome, Hirschsprung disease, and slow transit constipation.
The adult intestine is known to possess neuronal progenitors, but their role and the mechanisms that activate
them are unknown. We and others have observed the birth of new neurons in specific experimental injury
models, including intestinal inflammation, GI infection, and following focal neuronal ablation. This neurogenic
response can serve to replace neurons lost to injury, but it can also produce neuronal hyperplasia which can
have significant pathologic consequences. Enteric neurogenesis is thus a double-edged sword that can be
leveraged for a beneficial effect but needs to be modulated to limit its consequences. Our preliminary results
suggest that experimental colitis in rodents promotes enteric glial cells to undergo a neurogenic transition via a
5-HT4-dependent pathway. However, this process is poorly understood. The overall objective of this proposal
is to understand the mechanisms underlying postnatal enteric neurogenesis and its role in GI health and
disease. To achieve this goal, we propose the following specific aims: (1) identify the downstream pathways
that are activated by 5-HT4 signaling and lead to glial differentiation into neurons; (2) characterize the
subpopulations of glial cells present in the intestine and determine the genetic and epigenetic changes that
occur during the glia-to-neuron fate switch; and (3) leverage the intestine’s capacity for neurogenesis to treat
the hypoganglionic transition zone associated with Hirschsprung disease. A variety of methodologies will be
used to achieve these aims, including isolation and culture of enteric glia from reporter mice; in vitro assays
using dominant-negative mutants and pharmacologic inhibitors to determine the signaling pathways involved in
glial neurogenesis; single cell RNA seq to identify glial cell subpopulations; a dual reporter transgenic system
for live cell imaging of glia-to-neuron cell fate transition; analysis of the genetic and epigenetic changes
occurring during that transition; and induction of enteric neurogenesis in HSCR bowel to treat transition zone
hypoganglionosis. Successful completion of these experiments will significantly enhance our understanding of
the mechanisms underlying neurogenesis in the adult intestine, provide insights into the pathophysiology of
neurointestinal diseases, identify new targets to modulate neurogenesis in vivo, offer novel approaches for
expanding enteric neurons in the hypoganglionic transition zone of HSCR and in other neurointestinal
diseases, and improve the in vitro expansi...

## Key facts

- **NIH application ID:** 9895033
- **Project number:** 1R01DK119210-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ALLAN M GOLDSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,312
- **Award type:** 1
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895033

## Citation

> US National Institutes of Health, RePORTER application 9895033, Characterizing neurogenic progenitors in the adult intestine (1R01DK119210-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9895033. Licensed CC0.

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