Investigating the Role of MYH14 in Tension-Dependent Cardiomyocyte Hypertrophy

项目总结/摘要 心力衰竭是住院治疗的主要原因，也是医疗费用上涨的主要驱动因素。使用 系统遗传学的方法在小鼠中，我们以前已经确定了非肌肉肌球蛋白编码的基因 Myh 14作为心力衰竭的遗传修饰剂。使用基因修饰的Myh 14敲除小鼠模型，我们 通过正在进行的NIH K 08进一步证实了其在维持心脏稳态中的重要性 支持研究。作为K 08奖的一部分，我们已经确定了MYH 14在小鼠中的亚细胞定位。 小鼠心脏组织和新生大鼠心室细胞培养物。然而，其在维护 心脏内环境稳定仍然难以捉摸。 MYH 14又称非肌球蛋白Ⅱ-C（NMIIC），是非肌球蛋白Ⅱ家族的最新成员， 依赖ATP的分子马达家族。MYH 14是遗传性听力损失的确定致病基因 并且被认为是上皮顶端连接中的力的主要整合者， 形态发生和张力平衡。最近，MYH 14中的R941 L突变被证明是 以显性负性方式抑制线粒体分裂，特别是在细胞周边，并改变线粒体的结构。 患者成纤维细胞系中线粒体基因组的组织。除了定位在嵌入的 如先前文献所示，我们发现MYH 14在肋节处或其附近表达。我们 假设MYH 14可能是调节心脏对机械应激的适应性反应的关键因素。 该R 03提案描述了一项2年计划，详细说明MYH 14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MYH 10的关系， 信号和物理交互器。对MYH 14在心肌细胞中功能的基本了解将有助于 提供了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， 体内平衡机制在不同形式的心脏病中被破坏。最后，从这项研究中得到的启示 可能揭示了这种自我平衡系统如何被推动以促进健康对抗疾病。

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.