# Regulation of the actin filament pointed end dynamics in health and disease

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2021 · $85,270

## Abstract

Alterations in the thin filaments involved in cardiac/skeletal muscle contraction often produce
cardiomyopathies/nemaline myopathies with fatal consequences. Our long-term goal is to identify the
components and molecular mechanisms regulating actin architecture in muscle during normal development and
disease. In the proposal supported by the ongoing grant, our short-term goal is to determine the mechanisms of
how thin filament lengths are regulated by the actin filament pointed end binding proteins, leiomodin (Lmod) and
tropomoduin (Tmod). Polymerization at the pointed end determines thin filament length and is regulated directly
by the binding of Tmod and Lmod. This binding is enhanced by the integral thin filament component,
tropomyosin. We hypothesize that maintenance of thin filament length requires the antagonistic action of Tmod
and Lmod; that is, the role of Tmod is to prevent elongation at the pointed end while Lmod allows elongation.
We also predict that Tmod and Lmod binding and action at the pointed end is determined by different
arrangements of their tropomyosin- and actin-binding sites. In our submitted renewal proposal, we will evaluate
how Lmod and Tmod affect the formation and then the structure of the thin filament. We will test our recently
proposed molecular mechanism for the Lmod/Tmod-dependent regulation of the pointed end of the thin
filaments. We will also study the structural and functional consequences of Lmod binding to sides of the already
formed thin filaments. Finally, we will establish mechanisms of regulation of Lmod functions. Our data will provide
a comprehensive identification of critical components of the regulatory mechanisms underlying thin filament
assembly and maintenance in health and disease.The proposed experiments will connect Lmod-related thin
filament alterations with familial myopathies. A better understanding of thin filament function and of its regulation
is critical to better understand muscle disease pathogenesis, to improve diagnostics and to potentially identify
novel drug targets.

## Key facts

- **NIH application ID:** 10387989
- **Project number:** 3R01GM120137-04S1
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Carol C Gregorio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $85,270
- **Award type:** 3
- **Project period:** 2017-06-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387989

## Citation

> US National Institutes of Health, RePORTER application 10387989, Regulation of the actin filament pointed end dynamics in health and disease (3R01GM120137-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10387989. Licensed CC0.

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