# Defining and modeling the cellular interactions for rhythmic colon motility

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $490,597

## Abstract

ABSTRACT: Continuous colon motility is critical for the overall health and survival of an organism and results
from activity in the enteric nervous system (ENS) and interstitial cells of Cajal (ICC) that are electrically-coupled
to smooth muscle. Although these cellular components have been individually studied in detail, how they interact
to coordinate motility across the length of colon is not well understood. Two motor patterns are measured
experimentally: (1) ‘ripple’ contractions produced by ICC slow waves of depolarization, and (2) colon migrating
motor complexes necessary for propulsion of fecal contents that require ENS activity. Existing models of colon
motility are focused on distal regions where distension from a fecal pellet activates intrinsic sensory neurons (or
IPANs) that excite ENS motor neurons for oral contraction and anal relaxation of smooth muscles; the forward
movement of the pellet then distends the adjacent segment, activates another IPAN, and this ‘neuromechanical
loop’ ensures propagation and propulsion of fecal contents. However, these models do not explain the regular
rhythm of colon motor complexes, which occur every 2-5 min, or how they are first initiated in the proximal colon
where fecal pellets have not yet formed. Unlike motor complexes that reach distal regions only when sensory
input is applied, spontaneous, rhythmic motor complexes occur in proximal regions regardless of luminal content,
stretch, or distension, indicating that the proximal colon has unique pacemaker capabilities that determine the
rhythm of motor complexes. The objective for this project is to determine and model the cellular interactions
unique to the proximal colon that are responsible for generating rhythmic motor complexes in normal and
inflamed conditions. We hypothesize that rhythmic motor complexes are due to cyclical interactions among ICC,
IPANs and motor neurons of the ENS, and that dysmotility during inflammation is due to dysregulation of these
interactions. To test this and address knowledge gaps, we will use optogenetics, calcium imaging, in situ
immunofluorescence, and computational modeling to define the cell-to-cell interactions responsible for
spontaneous, rhythmic motor complexes produced in the proximal colon and determine the cellular components
that contribute to dysrhythmic motility following inflammation. Aim 1 will determine the mechanical sensitivity of
proximal colon IPANs to ICC-generated ripple contractions. Aim 2 will define the ‘ENS neural program’ activated
by IPANs that produces motor complexes in proximal colon. Aim 3 will determine the effect of ENS activity on
ICC slow waves and ripple contractions. Each Aim will collect data from normal and inflamed colons, and findings
will be incorporated into our model to computationally test whether predictions can be made regarding motility
behavior based on changes in cellular activity. Thus, these studies will yield a novel computational model that
will help identif...

## Key facts

- **NIH application ID:** 10920387
- **Project number:** 5R01DK136906-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Kristen Michelle Smith-Edwards
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $490,597
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10920387

## Citation

> US National Institutes of Health, RePORTER application 10920387, Defining and modeling the cellular interactions for rhythmic colon motility (5R01DK136906-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10920387. Licensed CC0.

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