Mechanical Load Effects on Cardiac Function and Heart Diseases

意义：每次心跳时，心肌细胞都会产生收缩力，将血液泵入循环 抵抗机械负荷。心肌细胞也能感知负荷变化，并调节收缩力， 心输出量病理条件下的过度超负荷导致心脏病，如心律失常， 心衰然而，在分子和细胞机制方面仍然存在基本的知识差距， 心肌细胞中的机械转导，以及机械应力相关心脏的治疗 疾病（例如，高血压诱发的心律失常和心力衰竭、DCM、HFpEF）的治疗迄今为止受到严重限制。 创新：以前使用无负荷心肌细胞的实验在很大程度上忽略了机械负荷对心肌细胞的影响。 调节心肌细胞。我们将开发创新的Cell-in-Gel-TR技术来控制机械负载 在单细胞水平上。我们的研究表明，细胞收缩时的机械负荷可以反馈， 调节兴奋-Ca ~（2+）信号-收缩（E-C）耦合中的3个动力学系统;关闭这些 反馈回路使心肌细胞能够响应负荷变化自动调节E-C耦合。这 我们将在R35研究中探索概念创新，以了解机械载荷如何影响 心肌细胞功能和心脏病。研究计划：我研究的中心主题是阐明 E-C中的3个动力系统如何耦合前馈和反馈来控制心脏功能， 动态调节智能泵。在R35中，我们将扩大和深化我们的研究，超越2 R 01的范围， 机械传导机制和功能后果的多尺度系统研究。（一） 分子水平的研究，以破译机械-化学-电-转导（MCET）途径，确定关键 参与者，并确定分子机制。(2)细胞水平研究，以研究机械负荷 调节兴奋-Ca ~（2+）信号-收缩耦合的动力学系统。(3)心脏水平研究， 探讨机械负荷如何调节完整心脏功能。(4)研究心脏病以了解 病理性超负荷为何/如何导致心脏重塑、心律失常和心力衰竭。这四个部分是 旨在相互通报和增强，以提供关于机械转导如何 这些通路在分子水平上起作用，在细胞水平上整合，并表现为心脏的自动调节能力 收缩性响应于健康和疾病中的机械负荷变化。能力和适应性： 我的研究力量源于跨学科的方法。我的研究历史表明 通过结合物理、化学和生物学的严格方法开发新技术的记录。 在R35，我将继续开发创新的解决方案，并使用尖端技术来实现 转型研究目标。预期成果和影响：研究成果将改变范式 心脏E-C耦合的自动调节模型，这将打开新的概念框架，了解 机械负荷如何影响心脏病，并帮助确定开发新疗法的分子靶点。

Significance: In every heartbeat, cardiac muscle cells generate contractile force to pump blood into circulation against a mechanical load. Cardiomyocytes also sense load changes and adjust the contractility to maintain cardiac output. Excessive overload in pathological conditions leads to heart diseases such as arrhythmias and heart failure. However, fundamental knowledge gaps still exist in the molecular and cellular mechanisms of mechano-transduction in cardiomyocytes, and therapeutic treatments for mechanical stress associated heart diseases (e.g., hypertension induced arrhythmias and heart failure, DCM, HFpEF) are severely limited to date. Innovations: Previous experiments using load-free cardiomyocytes largely missed mechanical load effects on regulating cardiomyocytes. We will develop an innovative Cell-in-Gel-TR technology to control mechanical load at the single-cell level. Our studies reveal that the mechanical load on the cell during contraction can feedback to regulate the 3 dynamic systems in excitation-Ca2+ signaling-contraction (E-C) coupling; closing these feedback loops enables the cardiomyocyte to autoregulate E-C coupling in response to load changes. This conceptual innovation will be explored in our R35 research to understand how mechanical load affects cardiomyocyte function and heart diseases. Research Plan: The central theme of my research is to elucidate how the 3 dynamic systems in E-C coupling feedforward and feedback to control the heart function as a dynamically regulated smart pump. In R35, we will expand and deepen our research beyond the 2 R01s to do multi-scale systematic studies of the mechano-transduction mechanisms and functional consequences. (1) Molecular level study to decipher mechano-chemo-electro-transduction (MCET) pathways, identify the key players, and determine molecular mechanisms. (2) Cell level study to investigate how mechanical load regulates the dynamic systems of excitation-Ca2+ signaling-contraction coupling. (3) Heart level study to probe how mechanical load regulates the intact heart function. (4) Study of heart diseases to understand why/how pathological overload leads to cardiac remodeling, arrhythmias, and heart failure. These 4 parts are designed to inform and enhance one another to provide a comprehensive view on how mechano-transduction pathways work at molecular level, integrate at the cell level, and manifest to the heart’s ability to autoregulate contractility in response to mechanical load changes in health and diseases. Capability and Adaptability: The strength of my research stems from interdisciplinary approach. The history of my research shows a strong track record in developing new technologies by combining rigorous methods in physics, chemistry, and biology. In R35, I will continue developing innovative solutions and to use cutting-edge technologies to achieve the transformative research goals. Expected Outcome and Impact: The research outcome will shift the paradigm of cardiac E-C coupling to Autoregulatory Model, which will open new conceptual framework for understanding how mechanical load affects heart diseases and help identify molecular targets for developing new therapies.