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Modeling myosin mechanobiology towards understanding the mechanisms of hypertrophic cardiomyopathy

模拟肌球蛋白力学生物学以了解肥厚型心肌病的机制

基本信息

批准号：
10301337
负责人：
Alison Schroer Vander Roest
金额：
$ 16.63万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301337
关键词：
ATP phosphohydrolase Adhesions Advisory Committees Affect Alleles Area Automobile Driving Award Biological Models Biomechanics Biomedical Engineering CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiac Myosins Cell Adhesion Cell-Cell Adhesion Cells Cellular biology Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Computer Models Contracts Cues Development Disease Disease Progression Elements Engineering Environment Event Extracellular Matrix Fibroblasts Fibrosis Fluorescence Resonance Energy Transfer Functional disorder Gene Expression Generations Genes Genotype Goals Health Heart Heart Diseases Heart failure Heritability Heterogeneity Human Hypertrophic Cardiomyopathy Hypertrophy ITGB3 gene In Vitro Induced Mutation Integrins Intercellular Junctions Kinetics Knowledge Lead Link MAP Kinase Gene Measurement Measures Mechanics Mediator of activation protein Mentors Mentorship Modeling Molecular Molecular Biology Mutation Myofibrils Myofibroblast Myosin ATPase Myosin Heavy Chains Organ Pathologic Pathway interactions Patients Pharmacotherapy Phase Phenotype Point Mutation Positioning Attribute Production Proteins Regulation Research Research Support Research Training Role Sarcomeres Severity of illness Signal Pathway Signal Transduction System Technical Expertise Techniques Testing Therapeutic Tissues Traction Force Microscopy Training Universities Validation Variant Vinculin beta-Myosin career career development disease phenotype disease-causing mutation experience extracellular improved in silico in vivo individualized medicine induced pluripotent stem cell innovation insight molecular phenotype mutant new therapeutic target novel research and development response sensor single molecule skill acquisition skills species difference tool transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY: This proposed project focuses on understanding how mutations in beta cardiac myosin with diverse and often opposing effects on myosin molecular function contribute to similar disease phenotypes of hypertrophic cardiomyopathy (HCM): cardiomyocyte (CM) hypertrophy, hypercontractility, and tissue fibrosis. Understanding disease mechanisms and the heterogeneity of phenotypes across multiple scales (molecular, cellular, and clinical) will enable the development of better and more individualized therapies for patients with HCM. The first aim of this proposal will clarify the mechanisms by which altered intracellular forces affect intracellular signaling and CM hypertrophy. The second aim will use computational modeling to examine how alterations to interrelated parameters of myosin function change force production temporally and spatially. The third aim will define how altered extracellular mechanics affect CM and cardiac fibroblast phenotypes. The proposal uses several innovative molecular, cellular, bioengineering, and computational modeling tools to examine and contextualize the role of altered cellular mechanics in driving changes in cardiac cell phenotypes. CRISPR/Cas9 gene editing in human induced pluripotent stem cells provides a model system to investigate the effects of specific mutations in a dynamic cellular context. Micropatterned engineered platforms will be used to improve myofibril alignment and allow direct measurement of intracellular force production by traction force microscopy. Molecular biology and transcriptomic techniques will be used to measure changes in intracellular signaling and gene expression in response to mechanical perturbation. Another innovation is the novel application of a vinculin tension sensor FRET probe to directly measure intracellular forces at sarcomere Z disks and at cellular adhesions. Together these platforms will allow direct validation of temporal and spatial cellular forces predicted using computational modeling (molecular myosin models and cell-specific finite element models). Finally, investigating the effect of altered extracellular mechanics on CM function and cardiac fibroblast activation in engineered environments will give insights into the effects of fibrotic remodeling. The research and career development training plans will enable the transition of Dr. Vander Roest to an independent career. During the mentored (K99 phase) of this proposal, Dr. Vander Roest will develop technical skills in molecular biomechanics, FRET measurements, and transcriptome analysis, and expand her skills in computational modeling in the context of cardiac disease. This training will take place at Stanford University, under the mentorship of Drs. Bernstein and Spudich, as well as an expert trans-disciplinary advisory committee, including 2 experts in computational modeling (Drs. Regnier and Campbell). The development of these skills will support the research plan for the independent phase of this project, combining new skills and experience gained during this award with Dr. Vander Roest’s past experience in myofibroblast mechanobiology to facilitate a successful transition to independence.

项目概述：这个项目的重点是了解β心肌肌球蛋白的突变如何