# REGULATION OF THE ACTIN FILAMENT POINTED END DYNAMICS IN HEALTH AND DISEASE

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2024 · $570,596

## Abstract

In striated muscles, actin thin filament architecture is critical for efficient contractile activity, and
alterations in thin filament integrity are linked to severe and often lethal skeletal and cardiac
muscle diseases. Our long-term goal is to identify the components and molecular mechanisms
regulating actin architecture in striated muscle during normal development and disease. Our
short-term goal is to evaluate how actin-binding proteins of the tropomodulin family (e.g. leiomodin
or Lmod and tropomoduin or 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. We propose three aims to identify
underlying molecular mechanisms of the full spectrum of Lmod and Tmod functions: (1) to
decipher the role of Lmod in the maintenance of proper thin filament lengths via pointed end
regulation; (2) to establish the role of Lmod’s actin-binding sites in thin filament activation; (3) to
test the hypothesis that Lmod functions are regulated by Ca2+. By employing high resolution
cryogenic electron microscopy (cryo-EM) in conjunction with 3-dimensional nuclear magnetic
resonance and Förster resonance energy transfer), we will recreate the full picture of Ca2+-
dependent Lmod interactions with the thin filament and reveal the biological significance of these
interactions. The robustness of structural models will be evaluated by monitoring of development
and contractility of cardiac and skeletal muscles in knockout mice in vivo via the identification and
utilization of mutations specifically affecting newly discovered Lmod’s and Tmod’s functionalities.
To achieve these goals, we established a powerful multidisciplinary collaboration between the
Kostyukova laboratory at the Washington State University (expert in protein structure, biochemical
and biophysical properties of actin-binding proteins), the Gregorio laboratory at the University of
Arizona (expert in the molecular, cellular and developmental biology of myofibril assembly) and
the Galkin laboratory at the Eastern Virginia Medical School (expert in high resolution cryo-EM of
actin complexes). Our data will provide a comprehensive identification of critical components of
the regulatory mechanisms underlying thin filament assembly and maintenance in health and
disease.

## Key facts

- **NIH application ID:** 10908577
- **Project number:** 5R01GM120137-08
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Vitold Galkin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $570,596
- **Award type:** 5
- **Project period:** 2017-06-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908577

## Citation

> US National Institutes of Health, RePORTER application 10908577, REGULATION OF THE ACTIN FILAMENT POINTED END DYNAMICS IN HEALTH AND DISEASE (5R01GM120137-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10908577. Licensed CC0.

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