# From proteins to cells to tissues: A multi-scale assessment of biomechanical regulation by the myosin molecular motor

> **NIH NIH RM1** · STANFORD UNIVERSITY · 2021 · $20,915

## Abstract

The overarching goal of the parent project is to use myosin as a model system in which to address the
fundamental biological question of how alterations in tissue organization and function can arise from often
subtle changes in function at the molecular level. Force generation by myosin is required not only for the
physiological functions of skeletal muscle and the heart, but also for the proper development and maintenance
of these tissues during embryogenesis and beyond. Our team aims to develop a detailed mechanistic
understanding of how force generation by myosin acts to regulate muscle tissue development and
homeostasis. We examine this general question through the lens of asking how seemingly small changes in
the activity of individual myosin molecules can drive dramatic changes in tissue-level organization and function,
for example in the context of inherited disease. In Aim 1, we will determine how structural changes in myosin
affect the chemo-mechanical properties of the myosin-actin interaction for individual and small assemblies of
motor proteins. This aim will leverage innovative techniques developed by our team to quantify biomechanical
changes induced by myosin mutations at the single molecule level and the corresponding consequences for
sarcomere-level structure and function. In Aims 2 and 3, we will determine how changes in myosin kinetics and
force production influence the growth, maturation, and function of cells and tissues, using cardiomyocytes and
skeletal myocytes as model systems. These aims will leverage CRISPR-editing to introduce myosin mutations
in isogenic hiPSC-derived cardiac and skeletal myocytes. We will then be able to compare biomechanical
alterations at the individual molecule level with those in sub-cellular organelles (myofibrils), cells and micro-
tissues. We expect to answer basic mechanistic questions as to how alterations in protein structure and
function affect cell and tissue function, changing force and plasticity, and provide a window into understanding
how cells adapt to alterations in changing mechanical forces. We will then be positioned to utilize our hiPSC
platforms for high-throughput screens to develop novel therapies targeted to phenotypic subgroups of myosin
mutations. Another major goal of our Research Program is to support Early Stage Investigators (ESI). We will
support pilot studies from ESI investigators that explore innovative research questions relevant to our
Research Program. Critical to the NIGMS mission, our team’s multi-disciplinary integrated approach, spanning
the scale from individual molecules to sub-cellular structures to whole cells to engineered micro-tissues, will
serve as a prototype for teams undertaking future studies using hiPSCs to explore other biological protein
assemblies, using human disease-producing mutations as perturbations to define their molecular and
functional mechanisms across organ systems.

## Key facts

- **NIH application ID:** 10291393
- **Project number:** 3RM1GM131981-02S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Daniel Bernstein
- **Activity code:** RM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $20,915
- **Award type:** 3
- **Project period:** 2019-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10291393

## Citation

> US National Institutes of Health, RePORTER application 10291393, From proteins to cells to tissues: A multi-scale assessment of biomechanical regulation by the myosin molecular motor (3RM1GM131981-02S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10291393. Licensed CC0.

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