# Actin-myosin contractility promotes the development of chronic bronchitis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $419,120

## Abstract

PROJECT SUMMARY
Chronic Obstructive Pulmonary Disease (COPD) is the 3rd leading cause of death in the US with a large subset
of patients exhibiting chronic bronchitis. At this time we have no medications to cure chronic bronchitis (CB). In
the U.S., cigarette smoke (CS) is the primary insult, leading to CB; yet, we do not understand how CS alters the
epithelium to promote the development of mucus. In our work, we found that chronic CS causes stiffening of
the epithelial cell in order to impact on its shape and decrease cell-cell adhesion proteins such as E-cadherin, to
prevent the formation of contacts between neighboring cells. In this proposal, we will decipher the effects of
altered actin-myosin II contractility. We propose that this increase in cell contractility decreases the polarity of
the epithelial cell to promote cell-signaling events, including the activation of the epithelial growth factor receptor
(EGFR). EGFR activation, in turn, leads to changes associated with chronic bronchitis, such as the increase in
Muc5AC production. We propose to study pharmacologic interventions to alter actin-myosin contractility to
study its effects on E-cadherin, cell-cell adhesion, cell polarity with EGFR activation and Muc5AC production. In
Aim 1, we will determine if CS causes myosin II-driven increases in actin-myosin contractility to decrease
membrane E-cadherin and disrupting cell-cell adhesion. Specifically, we will dissect the molecular mechanisms
by which CS increases actin-myosin contractility, and determine if manipulating this increase will alter E-
cadherin levels and cell-cell adhesion. In Aim 2, we will determine if CS-induced increased actin-myosin II
contractility causes the epithelial cell to increase aberrant EGFR activation. Specifically, we will determine if
increased contractility alters the polarity of the epithelium to promote EGF receptor-ligand interaction on either
the apical or basolateral membrane to increase EGFR activation. In Aim 3, we will determine if, in a mouse
model, decreasing the actin-myosin contractility will reverse EGFR activation and Muc5AC production by the
epithelium after chronic CS. We will determine if inhibiting actin-myosin II contractility in vivo prevents or
abrogates the CS-induced increase in Muc5AC and mucin production evident in mice after chronic CS
exposure. We have found that E-cadherin knockdown promotes EGFR activation in mice. Using our newly
established model to knockdown E-cadherin in the mouse lung epithelium, we will assess if actin-myosin
contractility is upstream of decreases in E-cadherin to cause EGFR activation and increased Muc5AC. This is a
five year grant proposal from an Early Stage Investigator.

## Key facts

- **NIH application ID:** 9891079
- **Project number:** 5R01HL124099-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Venkataramana K Sidhaye
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,120
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891079

## Citation

> US National Institutes of Health, RePORTER application 9891079, Actin-myosin contractility promotes the development of chronic bronchitis (5R01HL124099-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9891079. Licensed CC0.

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