# Unconventional myosins and the regulation of gut barrier integrity and restitution during inflammation

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $452,637

## Abstract

PROJECT SUMMARY: Disruption of the intestinal epithelial barrier in patients with inflammatory bowel
diseases (IBD) involves disassembly of epithelial tight junctions (TJ) and adherens junctions (AJ), along with
formation of mucosal wounds due to excessive epithelial cell death. Restoration of the gut barrier (epithelial
restitution) is critical for achieving remission of the disease and it involves mucosal wound healing and AJ/TJ
reassembly. Both processes are mediated by common molecular events, most notably, dramatic remodeling of
the epithelial actomyosin cytoskeleton. An unconventional myosin 18A (Myo18A) is a unique PDZ-domain
containing scaffolding protein that acts as an essential regulator of actin filaments and their motor, non-muscle
myosin II (NM II). Myo18A is known to control neuronal and muscle morphogenesis, as well as tumor growth
and dissemination, however its functions in the gut have not been previously investigated. Our preliminary data
suggests that Myo18A is abundantly expressed in normal human intestinal epithelium and it is a novel
component of epithelial junctions, Furthermore, Myo18A depletion leads to various functional defects, including
disruption of the epithelial barrier, attenuation of wound healing and impairment of 3-D epithelial
morphogenesis. Importantly, we observed a marked downregulation of Myo18A expression in the intestinal
epithelium of ulcerative colitis patients. This exciting preliminary data provides a strong scientific premise for
the following innovative hypothesis: Myo18A is a novel regulator of the intestinal epithelial barrier
integrity and restitution, and its depletion promotes gut leakiness and inhibits mucosal healing in IBD
patients.
This hypothesis will be tested in the following Aims: (1) to determine the roles of Myo18A in the regulation of
intestinal epithelial cell migration and ECM adhesion; (2) to delineate the mechanisms of Myo18A-dependent
assembly of the epithelial barrier and establishment of the apico-basal cell polarity; 3) to examine the roles of
Myo18A in regulating disruption and restitution of the intestinal epithelial barrier in vivo. The Aims will be
accomplished by studies utilizing in vitro intestinal epithelial cell monolayers, ex vivo colonic organoids
generated from IBD mucosa and in vivo murine models of epithelial injury and restitution. Roles of Myo18A will
be examined by a combination of functional (permeability measurements, wound healing), biochemical
(immunoblotting, detergent fractionation), imaging (FRET biosensors, super-resolution microscopy), and
genetic (CRISPR/Cas9 gene editing, overexpression of deletion mutants, knockout mice) approaches.
Significance: the proposed study will yield novel insights into the mechanisms that regulate intestinal epithelial
injury and restitution during inflammation. It will also identify new therapeutic targets to prevent breakdown and
enhance reparation of the gut barrier in patients with digestive diseases.

## Key facts

- **NIH application ID:** 10094455
- **Project number:** 1R01DK126702-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Andrei Ivanovich Ivanov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $452,637
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094455

## Citation

> US National Institutes of Health, RePORTER application 10094455, Unconventional myosins and the regulation of gut barrier integrity and restitution during inflammation (1R01DK126702-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10094455. Licensed CC0.

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