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

> **NIH NIH RM1** · STANFORD UNIVERSITY · 2022 · $2,075,915

## Abstract

PROJECT SUMMARY/ABSTRACT
The overarching goal of this 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:** 10396504
- **Project number:** 5RM1GM131981-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Daniel Bernstein
- **Activity code:** RM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,075,915
- **Award type:** 5
- **Project period:** 2019-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396504

## Citation

> US National Institutes of Health, RePORTER application 10396504, From proteins to cells to tissues: A multi-scale assessment of biomechanical regulation by the myosin molecular motor (5RM1GM131981-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10396504. Licensed CC0.

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