# Cooperative targeting of pharmacomechanical coupling and the actin cytoskeleton to regulate ASM contraction

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $474,337

## Abstract

Project Summary
 Effective asthma management requires regulating airway smooth muscle (ASM) contractile state to avoid or
reverse bronchoconstriction. Whether this is attempted by use of direct bronchodilators (e.g., β-agonists), by
anti-inflammatory agents (e.g., corticosteroids), or some combination of both, too often management is lacking,
as an estimated 55% of all asthmatics have suboptimal control. All current bronchodilator drugs have limitations
which respect to efficacy, and safety issues still persist with the most frequently used class of bronchodilator
drugs- long-acting β-agonists (LABAs). We submit that the limitations of bronchodilator drugs can be overcome
by an approach that targets the 2 most powerful regulators of ASM contractile state: pharmacomechanical
coupling and the actin cytoskeleton. We hypothesize that combinations of beta-agonists (that primarily target
pharmacomechanical coupling) and drugs that specifically target the actin cytoskeleton can be highly efficacious
bronchodilators, with a functional cooperatively that enables lower drug doses and therefore a better safety
profile. Three aims are proposed to test this hypothesis. In Aim 1, we will establish, using cell, tissue, and in vivo
models of ASM contraction, the cooperative nature of combined targeting of pharmacomechanical coupling and
actin polymerization, and identify optimal combinations of beta-agonists and cytoskeleton-targeting drugs that
relax ASM. In Aim 2, we will determine the mechanistic basis for this functional cooperativity by characterizing
the effects of these drugs on signaling intermediates and outcomes that control cross bridge cycle (myosin light
chain kinase and phosphatase phosphorylation) or actin polymerization state (F/G actin ratio), and on the
upstream signals that regulate these outcomes. Lastly, in Aim 3 we will assess the effect of asthma pathobiology
on the efficacy of combining β-agonists and actin cytoskeleton-targeting drugs in inhibiting ASM contraction and
airway resistance, by employing cell and tissue model systems derived from cells/tissues from human
asthmatics, or in which asthma pathobiology is imposed either in vitro/ex vivo (to cells, tissue), or in vivo (2
differrent in vivo murine models). The proposed studies performed by 3 established PIs with complementary
expertise represent an innovative approach to establish an asthma management strategy that overcomes the
current limitations of efficacy and safety. Moreover, the proposed mechanistic studies will provide new insight
into how to optimally disrupt the cooperation between cross bridge cycling and cytoskeleton stiffening that
generates tension in the ASM cell.

## Key facts

- **NIH application ID:** 9983151
- **Project number:** 5R01HL145392-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** RAMASWAMY KRISHNAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $474,337
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983151

## Citation

> US National Institutes of Health, RePORTER application 9983151, Cooperative targeting of pharmacomechanical coupling and the actin cytoskeleton to regulate ASM contraction (5R01HL145392-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983151. Licensed CC0.

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