Investigating the Role of MYH14 in Tension-Dependent Cardiomyocyte Hypertrophy

研究 MYH14 在张力依赖性心肌细胞肥大中的作用

• 批准号: 10677677
• 负责人: Jessica J Wang
• 金额: $ 7.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10677677
• 关键词: Actins; Adult; Apical; Area; Award; Binding Sites; Biophysics; Cardiac; Cardiac Myocytes; Cell Culture Techniques; Cells; Chronic; Co-Immunoprecipitations; Cues; Cytoplasm; Development; Disease; Dominant-Negative Mutation; Elasticity; Embryo; Environment; Epithelium; Extracellular Matrix; Family; Fibroblasts; Filament; Future; Genes; Genetic; Genetic Screening; Growth; Health Care Costs; Health Promotion; Heart; Heart Abnormalities; Heart Hypertrophy; Heart failure; Homeostasis; Hormonal; Hospitalization; Hypertrophy; Integrins; Intercalated disc; Investigation; Isoproterenol; Knockout Mice; Laboratories; Lead; Light; Link; Literature; Location; Maintenance; Mass Spectrum Analysis; Mechanical Stress; Mechanics; Mediating; Microscopy; Mitochondria; Molecular Motors; Morphogenesis; Mus; Muscle; Mutation; Myosin ATPase; Myosin Light Chains; Myosin Type II; Neonatal; Pathologic; Pathology; Patients; Physiological; Play; Preparation; Protein Isoforms; Proteins; PubMed; Publications; Rattus; Regulation; Research; Research Support; Role; Sarcomeres; Signal Transduction; Stains; Stretching; System; Talin; Thick; Time; Tissues; Transcript; United States National Institutes of Health; Ventricular; Vinculin; causal variant; comparison control; genetic approach; heart cell; hemodynamics; hereditary hearing loss; hormonal signals; improved; insight; mechanotransduction; member; mitochondrial genome; mouse model; non-muscle myosin; non-muscle myosin heavy chain-B; novel; outcome prediction; pressure; response; stressor; superresolution microscopy; tool; transcriptome sequencing; ultra high resolution

PROJECT SUMMARY / ABSTRACT Heart failure is a leading cause of hospitalization and a primary driver behind rising healthcare costs. Using a systems genetics approach in mice, we have previously identified a non-muscle myosin encoded by the gene Myh14 as a genetic modifier of heart failure. Using a genetically modified Myh14 knockout mouse model, we have further validated its importance in the maintenance of cardiac homeostasis through ongoing NIH K08 supported research. As a part of the K08 award, we have determined the subcellular localization of MYH14 in murine heart tissue and neonatal rat ventricular cell culture. However, its specific roles in maintenance of cardiac homeostasis remains elusive. MYH14, also known as non-muscle myosin II-C (NMIIC), is the newest member of the non-muscle myosin II family of ATP-dependent molecular motors. MYH14 is an established causal gene for hereditary hearing loss and is believed to be the master integrators of force within epithelial apical junctions, mediating epithelial tissue morphogenesis and tensional homeostasis. Recently, the R941L mutation in MYH14 was demonstrated to act in a dominant-negative fashion to inhibit mitochondrial fission, especially in the cell periphery, and to alter the organization of the mitochondrial genome in patient fibroblast lines. In addition to localization in the intercalated disc, as shown in prior literature, we found that MYH14 is expressed at or near the costameres. We hypothesize that MYH14 may be key player in modulating the heart’s adaptive response to mechanical stress. This R03 proposal describes a 2-year plan to detail MYH14’s subsarcolemmal and cytoplasmic localization, relationships with the other known non-muscle myosin in cardiomyocyte, MYH10, response to hormonal signals and physical interactors. Fundamental understanding of MYH14’s function in the cardiomyocytes will provide insights into how the cardiomyocyte responds to mechanical stress as well as hormonal signals that may modulate this response. Moreover, these insights will allow us to predict outcomes when such homeostatic mechanisms break down in different forms of cardiac pathologies. Finally, insights from this study may shed light how such homeostatic system may be nudge to promote health versus disease.

项目摘要 /摘要 心力衰竭是住院的主要原因，也是医疗保健费用上升的主要驱动因素。使用 在小鼠中，系统遗传学方法，我们以前已经确定了由基因编码的非肌肉肌球蛋白 MYH14是心力衰竭的遗传修饰符。使用转基因的MYH14敲除鼠标模型，我们 通过正在进行的NIH K08，进一步验证了其在维持心脏体内稳态的重要性 支持研究。作为K08奖的一部分，我们确定了MYH14的亚细胞定位 鼠心脏组织和新生大鼠心室细胞培养。但是，它在维护中的具体角色 心脏稳态仍然难以捉摸。 MYH14，也称为非肌肉肌球蛋白II-C（NMIIC），是非肌肉肌球蛋白II的最新成员 依赖ATP的分子电机家族。 MYH14是遗传性听力损失的既定因果基因 并被认为是上皮顶点内部力的主积分，介导上皮组织 形态发生和紧张稳态。最近，MYH14中的R941L突变被证明是行动的 以主导性的方式抑制线粒体裂变，尤其是在细胞外周中，并改变 在患者成纤维细胞系中线粒体基因组的组织。除了在插入中的本地化 碟片，如先前的文献所示，我们发现MYH14在服装师或附近表达。我们 假设MYH14可能是调节心脏对机械压力的自适应反应的关键参与者。 该R03提案描述了一项为期两年的计划，详细介绍了MYH14的亚属膜和细胞质定位， 与心肌细胞中其他已知的非肌肉肌球蛋白MyH10的关系，对马的反应 信号和物理互动器。对MYH14在心肌细胞中功能的基本了解将 提供有关心肌细胞对机械应力的反应以及马式信号的见解 可以调节此响应。此外，这些见解将使我们能够预测结果 稳态机制分解了不同形式的心脏病理。最后，这项研究的见解 可能会阐明这种稳态系统如何推动以促进健康与疾病。