Investigating the Role of MYH14 in Tension-Dependent Cardiomyocyte Hypertrophy

项目摘要/摘要 心力衰竭是住院的主要原因，也是医疗成本上升的主要驱动因素。使用 在小鼠的系统遗传学方法中，我们先前已经发现了一个由该基因编码的非肌肉肌球蛋白 Myh14是心力衰竭的遗传修饰物。使用转基因Myh14基因敲除小鼠模型，我们 通过正在进行的NIH K08进一步验证了其在维持心脏动态平衡方面的重要性 受资助的研究。作为K08奖的一部分，我们确定了MYH14在 小鼠心脏组织和新生大鼠心肌细胞培养。然而，它在维护 心脏动态平衡仍然难以捉摸。 MYH14又称非肌肉肌球蛋白II-C(NMIIC)，是非肌肉肌球蛋白II的最新成员 依赖于ATP的分子马达家族。MYH14是遗传性耳聋的已知致病基因 并被认为是上皮根尖连接内力的主要积分者，介导上皮组织 形态发生和张力动态平衡。最近，MYH14的R941L突变被证明起作用 以显性-负性方式抑制线粒体分裂，特别是在细胞外围，并改变 患者成纤维细胞系中线粒体基因组的组织。除了局部化外，还嵌入了 如先前的文献所示，我们发现MYH14在胞囊或其附近表达。我们 假设MYH14可能是调节心脏对机械压力的适应性反应的关键角色。 这份R03提案描述了一项为期两年的计划，以详细说明MYH14的S的肌膜下和细胞质定位， 与心肌细胞中已知的其他非肌肉肌球蛋白MYH10对激素反应的关系 信号和物理交互作用。对MYH14‘S在心肌细胞中作用的初步认识 提供对心肌细胞如何应对机械应激以及荷尔蒙信号的洞察 可以调节这种反应。此外，这些洞察力将使我们能够预测结果 动态平衡机制在不同形式的心脏病理中被破坏。最后，来自这项研究的见解 可能会揭示这样的动态平衡系统如何被推动以促进健康与疾病。

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.