# Pathophysiological remodeling of the enteric neuromuscular compartment in experimental spinal cord injury

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2021 · $333,138

## Abstract

ABSTRACT
The striking physical effects of spinal cord injury (SCI) are most obviously observed as a loss of motor control
and sensation below the level of injury. However, neurogenic bowel is one of the most prevalent and clinically
recognized comorbidities associated with SCI and is manifested as diminished colonic transit, constipation,
evacuation dyssynergy, and overflow incontinence. Colonic dysregulation is recognized as a lifelong physical
and psychological challenge for SCI patients and gravely impacts quality of life. The association of SCI with
storage and evacuation deficits promotes an inherent tendency to focus upon the loss of supraspinal regulation
of somatic and autonomic circuitry of the spinal cord. However, the GI tract is unique in that it has its own
extensive intrinsic nervous system, the enteric nervous system (ENS), and has the ability to function quasi-
autonomously. Normal colonic transit requires maintenance of the ENS and a syncytium of cells regulating
contraction of the smooth muscle to modulate intrinsic reflexes and coordinate gut activity. While the function
of the ENS is presumed to be preserved following SCI, the disruption of reflex colonic transit suggests
otherwise. While the pathophysiology of neurogenic bowel remains to be understood, studies focusing on GI
motility disorders suggest that a loss of enteric neurons, interstitial cells of Cajal (ICC) and fibroblast-like cells
(FLC) may be an underlying cause for the majority of these disorders. These cells form the neuromuscular
interface through which all smooth muscle activity is regulated. In this proposal we will use an animal model of
T3-SCI combined with molecular and cellular techniques as well as in vivo neurophysiological recordings in an
aim to define the mechanisms resulting in the loss of enteric nervous system-mediated colonic function post-
SCI. Our overarching hypothesis is that spinal cord injury induces colonic dysmotility by reducing the enteric
nervous system regulation. We will demonstrate that elevated levels of reactive oxygen species (ROS)
precedes the loss of enteric neuromuscular circuits and that ROS scavengers will rescue these cells. Based
upon our preliminary observations, we will test the hypothesis that 1) SCI decreases neuromuscular
transmission within the colonic smooth muscle after SCI; 2) SCI provokes the loss of ENS neurons, ICC and
FLC (neuromuscular remodeling of the colonic syncytium); and 3) SCI provokes impaired anti-oxidant defense
of the proximal and distal colon by evaluating elevated ROS levels within the colon and diminished levels of
heme oxygenase 1 (HO1), a key anti-oxidant molecule. Our initial expectation is that cholinergic excitatory
junction potentials and inhibitory (nitrergic and purinergic) junction potentials will be reduced, thus
demonstrating an enteric neuropathy provoking inhibition of colonic transit. These convergent tests of the
central hypothesis will provide valuable insight into the inflammato...

## Key facts

- **NIH application ID:** 10094085
- **Project number:** 5R01NS105987-03
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Gregory M. Holmes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,138
- **Award type:** 5
- **Project period:** 2019-03-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094085

## Citation

> US National Institutes of Health, RePORTER application 10094085, Pathophysiological remodeling of the enteric neuromuscular compartment in experimental spinal cord injury (5R01NS105987-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10094085. Licensed CC0.

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