# Smooth Muscle Mechanisms in Dynamic Airway Properties

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $459,613

## Abstract

Project Summary
 Airway smooth muscle (ASM) is a multifunctional tissue with complex physiologic properties. In addition
to its well-known role in regulating airway narrowing, ASM produces and secretes immunomodulatory
compounds, makes extracellular matrix (ECM) proteins, proliferates, and actively transitions between a
contractile and a synthetic state in response to multiple cues from its local environment. In the lung, the
extracellular environment of ASM cells may be modulated by both physiologic and pathophysiologic conditions
that can alter airway tissue structure, ECM composition, and the mechanical forces imposed on the airways, all
of which can trigger changes in the phenotype and physiologic responses of ASM to extracellular stimuli. The
mechanisms by which the phenotypic and physiologic properties of ASM cells are modulated in response to
extracellular conditions are critical for understanding the function of ASM under normal and pathophysiologic
conditions. The adhesion junctions that connect cells to the ECM within tissues are composed of large
multiprotein complexes termed adhesomes. Adhesomes play critical functions in cells that extend far beyond
their structural role: while they provide mechanical coupling between cells and their matrix environment, they
also enable cells to sense and respond to changes in the properties of their surrounding milieu. Our studies
have shown that contractile and inflammatory stimuli trigger the assembly of membrane adhesome complexes
in ASM tissues. These studies have led to a novel and detailed hypothesis for the molecular mechanisms for
adhesome assembly in ASM in response to physiologic stimuli. We propose that this process is a fundamental
process that is essential for the transduction of signals from diverse stimuli. However, the molecular
mechanisms by which adhesome assembly is regulated to modulate signals to different downstream effector
pathways are not understood. We hypothesize that S100A4, a member of the S100 protein family, and the α-
and β-parvins, components of the trimeric integrin-linked kinase (ILK)-PINCH-parvin complex, are key
intermediaries that play critical roles in adhesome assembly and in the differential activation of signaling
pathways by extracellular stimuli in ASM. We also propose that S100A4 acts extracellularly on ASM tissues to
promote inflammation and the synthetic phenotype. The proposed studies will employ ASM tissues and freshly
dissociated differentiated ASM cells to address three Specific Aims: 1) Determine the role of S100A4 in
regulating the response of ASM to contractile stimuli. 2) Determine the role of S100A4 as a mediator of
inflammation and evaluate its role in airway inflammation using a murine model. 3) Determine the molecular
mechanisms for the modulation of ASM phenotype in response to environmental and inflammatory stimuli.
These studies will provide new insights into the molecular mechanisms of signal transduction in ASM that are
likely to be bro...

## Key facts

- **NIH application ID:** 9923460
- **Project number:** 5R01HL029289-33
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Susan J. Gunst
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $459,613
- **Award type:** 5
- **Project period:** 1989-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923460

## Citation

> US National Institutes of Health, RePORTER application 9923460, Smooth Muscle Mechanisms in Dynamic Airway Properties (5R01HL029289-33). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9923460. Licensed CC0.

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