# Interstitial cells of Cajal in diabetic gastropathy

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $357,750

## Abstract

Disordered control of smooth muscle function is common in gastrointestinal diseases, which cost billions of
dollars in health care spending each year. Gastroparesis is one of the most significant manifestations of
gastrointestinal dysmotility, particularly in diabetes mellitus. However, therapeutic options are limited reflecting
incomplete understanding of cellular dynamics within the neuromuscular compartment. Previous research has
identified interstitial cells of Cajal (ICC) as the cell type most commonly affected in gastroparesis. ICC serve as
the physiological pacemaker for phasic contractile activity and mediate cholinergic and nitrergic neuromuscular
neurotransmission. Diabetic ICC depletion may arise from reduced insulin/IGF1 signaling and macrophage
action, which interfere with expression of the receptor tyrosine kinase Kit. A critical gap in our knowledge is the
lack of understanding of the fate of ICC lost from these insults. Cell death has been observed but not
consistently, prompting investigators to hypothesize ICC transdifferentiation, which could be reversible.
However, evidence of ICC survival following loss of Kit and other biomarkers has been elusive. Therefore, the
main objective of this project is to identify ICC fates, their mechanisms and reversibility in diabetes. Our central
hypothesis is that depletion of the ICC transcription factor Etv1 from reduced Kit signaling, together with
inhibition of “erasers” of repressive epigenetic marks due to disturbed mitochondrial metabolism, lead to
decommissioning and eventual silencing of super-enhancers that normally drive the transcription of genes
critical for ICC identity including Kit. These changes are accompanied by the upregulation of the closely related
gene Pdgfra, conferring on the surviving ICC the identity and function of “fibroblast-like cells” (FLC), which
mediate purinergic neuromuscular neurotransmission. Specific Aim 1 is to provide definitive evidence of ICC-
to-FLC phenotypic switch using in-vivo genetic lineage tracing and novel cell lines combined with phenotyping
by flow cytometry, immunofluorescence, Western blotting and transcriptome sequencing in cell populations
purified by fluorescence-activated cell sorting. Specific Aim 2 is to establish the epigenetic mechanisms
underlying ICC dedifferentiation and phenotypic conversion into FLC. We will analyze histone and DNA marks,
Etv1 binding and chromatin conformation in specific loci and genome-wide. We will perform mechanistic
studies using RNA interference (RNAi), as well as in-vitro CRISPR-Cas9-mediated and in-vivo Cre-mediated
genome editing combined with longitudinal analysis of gastric emptying. Specific Aim 3 is to determine the role
of succinate in the epigenetic repression of ICC genes using RNAi, in-vivo genome editing and the above
epigenomic and phenotyping methods. To facilitate translation of our findings, we will validate key mechanisms
in human tissues and attempt to restore ICC in mice using epigen...

## Key facts

- **NIH application ID:** 9966972
- **Project number:** 5R01DK058185-18
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Tamas Ordog
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,750
- **Award type:** 5
- **Project period:** 2002-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966972

## Citation

> US National Institutes of Health, RePORTER application 9966972, Interstitial cells of Cajal in diabetic gastropathy (5R01DK058185-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966972. Licensed CC0.

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