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The Role of Yes Associated Protein (YAP) in Hypertrophic Cardiomyopathy

Yes 相关蛋白 (YAP) 在肥厚性心肌病中的作用

基本信息

批准号：
10607984
负责人：
Orlando Chirikian
金额：
$ 3.99万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607984
关键词：
Actins Affect Biochemical Biomechanics Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cell Nucleus Cells Clinical Cytoplasm Cytoskeleton Desmin Development Disease Disease Progression Elements Environment Event Exhibits Fibrosis Generations Growth Heart Heart Diseases Homeostasis Human Hypertrophic Cardiomyopathy Hypertrophy In Vitro Individual Inherited Kinetics Knowledge Label Lead Measures Mechanical Stress Mechanics Mediating Microtubules Modeling Molecular Morphology Mutation Myosin ATPase Myosin Heavy Chains Nuclear Nuclear Protein Organ Organ Size Pathologic Pathway interactions Pharmaceutical Preparations Phenotype Point Mutation Production Protein Dynamics Proteins Regulation Research Research Training Role Signal Transduction Signaling Protein Stress Testing Therapeutic Traction Force Microscopy Troponin beta-Myosin disease phenotype extracellular genetic regulatory protein induced pluripotent stem cell derived cardiomyocytes insight mechanical signal mutant myosin-binding protein C novel optogenetics response tool transcriptome transmission process

项目摘要

Project Summary/Abstract Hypertrophy Cardiomyopathy (HCM) is the most prevalent hereditary cardiovascular disease – affecting 1 in 500 individuals. Advanced forms of the disease clinically present with hypercontractility, hypertrophy (enlargement of the organ and individual cardiomyocytes) and fibrosis. Several single-point mutations in b- myosin heavy chain (MYH7), Myosin Binding Protein C (MYBPC3), and Troponin (cTn) have been associated with HCM and increased contractility at the organ level. However, the kinetics at the molecular level remain unclear, as different sarcomeric protein mutations can result in increased, decreased, or unchanged force production. A knowledge gap persist in understanding how these altered kinetics at the molecular level lead to the more advanced hypertrophic phenotype of HCM at the cellular level. Interestingly, the Hippo Pathway has been demonstrated to be activated during developmental growth, quiescent during cardiac homeostasis, and reactivated in pathological growth (i.e. HCM). However its involvement in the disease, in particular the initiation of the hypertrophic phenotype, is poorly understood. Here, we aim to understand whether homeostatic mechanical signaling through the canonical growth regulator, Hippo-YAP, is altered 1) by changes in the biomechanics of single HCM mutant cardiomyocytes and 2) by alterations in the mechanical environment. We propose to use human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) genetically edited to harbor point mutations associated with HCM, as a reduce ordered model to study the relationship between mechanical signaling and hypertrophic growth. We will modulate mechanical stresses (i.e. diseased conditions) in healthy and diseased cardiomyocytes by treatment with inotropic drugs and culture in fibrotic-like stiff conditions and track the resulting signaling events by fluorescently labeling the key regulatory protein of the Hippo pathway (YAP). To further elucidate the mechanism by which YAP is contributing to the phenotypes of HCM we have developed a novel optogenetic tool, termed OptoYAP, which provides full temporal and spatial control of the Hippo pathway. Lastly we aim to understand the mechanism behind the reactivation of YAP in pathological conditions by perturbing the mechanical signaling by the nucleus. We hypothesize that 1) changes in force production alter the homeostatic mechano-signaling of the Hippo pathway to initiate cellular hypertrophy and 2) subsequent changes to the extracellular environment (stiffening) compounds this effect leading to a feedforward signal progressing the disease phenotypes. 3) pathological YAP signaling is driven by excessive force transmission by the cytoskeleton resulting in nuclear deformation. Our results will provide insights into HCM progression and provide a testbed for therapeutic options in treating HCM.

项目总结/文摘