Regulation of cardiac power output in health and disease

描述（由申请人提供）：心动周期是一个严格调节的过程，其中心脏在收缩期产生功率，然后在舒张期放松。如在心肌病患者中所见，该周期的功能障碍可导致心力衰竭和心律失常。在1：500的人群中发现的家族性心肌病主要是由参与肌肉收缩的肌节蛋白突变引起的。已经提出，这些突变影响心动周期的调节和心脏产生有效地将血液泵送到身体所需的力和功率的能力，导致心脏组织的重构和最终的心力衰竭。尽管有许多优雅的实验，但人们还不清楚分子尺度上的突变如何导致细胞收缩性和组织结构的变化。这项研究将有助于弥合我们对疾病发病机制的理解中的这一重大差距。通过结合单分子、整体动力学、干细胞工程和组织工程技术，我们的方法将使我们能够了解与心肌病突变相关的收缩性分子变化如何导致人类心脏组织中力和功率输出的改变。在资助的K99部分，我们将开发（1）一种新型的单分子体外试验，使我们能够模拟心脏的工作条件和（2）微机电设备中的人类心脏微组织，使我们能够检查人类心脏组织的收缩和结构特性。我们将使用分析来研究在健康心脏的分子、细胞和组织水平上调节力和功率输出的因素。重要的是，在K99部分开发的技术和方法将补充PI目前的技能，使他能够建立一个创新的研究计划。在赠款的R00部分，我们将应用这些新开发的技术来研究与人类心肌病相关的突变如何导致分子，细胞和组织水平的力量和功率输出的改变。这种多层次的方法将使我们对疾病的发病机制有前所未有的了解。此外，在资助期间开发的技术和方法应该为未来的研究开辟几条新的途径，因为PI过渡到完全独立的科学家。

DESCRIPTION (provided by applicant): The cardiac cycle is a tightly regulated process in which the heart generates power during systole and then relaxes during diastole. Dysfunction of this cycle, as seen in patients with cardiomyopathies, can lead to heart failure and arrhythmias. Familial cardiomyopathies, found in 1:500 members of the population, are caused primarily by mutation of sarcomeric proteins involved in muscle contraction. It has been proposed that these mutations affect the regulation of the cardiac cycle and the ability of the heart to generate the force and power necessary to effectively pump blood to the body, leading to restructuring of the heart tissue and eventual heart failure. Despite many elegant experiments, it is not well understood how mutations on the molecular scale lead to changes in cellular contractility and tissue organization. This research will help to bridge this major gap in our understanding of the disease pathogenesis. By combining single molecule, ensemble kinetic, stem cell engineering, and tissue engineering techniques, our approach will allow us to understand how molecular changes in contractility associated with cardiomyopathy mutations lead to alterations in force and power output in human cardiac tissue. During the K99 portion of the grant, we will develop (1) a novel single-molecule in vitro assay that will enable us to mimic working conditions in the heart and (2) human cardiac microtissues in microelectromechanical devices that will enable us to examine the contractile and structural properties of human cardiac tissue. We will use assays to study the factors that regulate force and power output at the molecular, cellular, and tissue levels in healthy hearts. Importantly, the techniques and approaches developed in the K99 portion of the grant will complement the PI's current skill set, enabling him to establish an innovative research program. During the R00 portion of the grant, we will apply these newly developed technologies to studying how mutations associated with human cardiomyopathies lead to alterations in force and power output at the molecular, cellular, and tissue levels. This multi-tiered approach will give us an unprecedented understanding of the disease pathogenesis. Moreover, the techniques and approaches developed during the funding period should open several new avenues for future studies as the PI transitions to being a fully- independent scientist.