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.

项目概要/摘要 心力衰竭是住院的主要原因，也是医疗费用上涨的主要原因。使用 通过在小鼠中进行系统遗传学方法，我们之前已经鉴定出由该基因编码的非肌肉肌球蛋白 Myh14 作为心力衰竭的遗传修饰剂。使用转基因 Myh14 敲除小鼠模型，我们 通过正在进行的 NIH K08 进一步验证了其在维持心脏稳态中的重要性 支持的研究。作为 K08 奖项的一部分，我们确定了 MYH14 的亚细胞定位 小鼠心脏组织和新生大鼠心室细胞培养。然而，它在维护方面的具体作用 心脏稳态仍然难以捉摸。 MYH14又名非肌肉肌球蛋白II-C (NMIIC)，是非肌肉肌球蛋白II的最新成员 ATP 依赖性分子马达家族。 MYH14 是遗传性听力损失的已知致病基因 并被认为是上皮顶端连接内力的主要整合者，介导上皮组织 形态发生和张力稳态。最近，MYH14 中的 R941L 突变被证明可以发挥作用 以显性失活方式抑制线粒体裂变，特别是在细胞外周，并改变 患者成纤维细胞系中线粒体基因组的组织。除了嵌入的本地化之外 如先前文献所示，我们发现 MYH14 在肋骨处或附近表达。我们 假设 MYH14 可能是调节心脏对机械应力的适应性反应的关键因素。 该 R03 提案描述了一个为期 2 年的计划，详细说明了 MYH14 的肌膜下和细胞质定位， 与心肌细胞中其他已知的非肌肉肌球蛋白 MYH10 的关系，对激素的反应 信号和物理交互器。对 MYH14 在心肌细胞中的功能的基本了解将有助于 提供有关心肌细胞如何响应机械应力以及激素信号的见解 可以调节这种反应。此外，这些见解将使我们能够预测结果 稳态机制在不同形式的心脏病理学中被破坏。最后，从这项研究中得到的见解 可能会揭示这种稳态系统如何促进健康对抗疾病。