Mechanical Load Effects on Cardiac Function and Heart Diseases

机械负荷对心脏功能和心脏病的影响

• 批准号: 10573078
• 负责人: Ye Chen-Izu
• 金额: $ 110.19万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2030-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573078
• 关键词: Affect; Arrhythmia; Biology; Cardiac; Cardiac Myocytes; Cardiac Output; Cells; Chemistry; Circulation; Contracts; Coupling; Disease; Feedback; Gel; Goals; Health; Heart; Heart Diseases; Heart failure; Hypertension; Knowledge; Mechanical Stress; Methods; Modeling; Molecular; Molecular Target; Myocardial dysfunction; Myocardium; Outcome; Outcomes Research; Pathologic; Pathway interactions; Physics; Pump; Recording of previous events; Research; STEM research; Signal Transduction; Technology; Therapeutic; Work; blood pump; design; dynamic system; experimental study; heart function; innovation; innovative technologies; interdisciplinary approach; mechanical load; mechanotransduction; new technology; novel therapeutic intervention; novel therapeutics; response

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.

意义：在每一个心跳中，心肌细胞都会产生收缩力，以将血液泵入循环 针对机械负载。心肌细胞还感知负载变化并调整收缩力以维护 心输出。在病理状况下超负荷导致心脏病，例如心律不齐和 心脏衰竭。但是，基本知识差距仍然存在于分子和细胞机制中 心肌细胞的机械转导和机械应力相关心脏的治疗治疗 疾病（例如，高血压引起的心律失常和心力衰竭，DCM，HFPEF）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错过了机械负载对 调节心肌细胞。我们将开发一种创新的电池内凝胶-TR技术来控制机械负载 在单细胞级别。我们的研究表明，收缩期间细胞上的机械负载可以反馈 在兴奋-CA2+信号 - 收集（E-C）耦合中调节3个动态系统；关闭这些 反馈环使心肌细胞能够自动调节E-C耦合，以响应负载变化。这 我们的R35研究将探讨概念创新，以了解机械负载如何影响 心肌细胞功能和心脏病。研究计划：我的研究的中心主题是阐明 E-C耦合前馈和反馈中的3个动态系统如何控制心脏功能 动态调节的智能泵。在R35中，我们将扩大和加深我们的研究以外的2 R01 对机理 - 转移机制和功能后果的多尺度系统研究。 （1） 分子水平研究对编译机械和化学电子转移（MCET）途径，识别钥匙 玩家，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-CA2+信号接收耦合的动态系统。 （3）心脏水平研究 探测机械负荷如何调节完整的心脏功能。 （4）心脏病的研究 为什么/病理超负荷如何导致心脏重塑，心律不齐和心力衰竭。这4个部分是 旨在互相告知和增强彼此，以提供有关机械转盘的全面观点 途径在分子水平上工作，在细胞水平集成，并表现出心脏自动调节的能力 响应健康和疾病的机械负荷变化的收缩力。能力和适应性： 我的研究力量源于跨学科的方法。我的研究历史表明了很强的 通过结合物理，化学和生物学中严格的方法来开发新技术的记录。 在R35中，我将继续开发创新的解决方案，并使用尖端技术来实现 变革性研究目标。预期结果和影响：研究结果将改变范式 心脏E-C耦合到自动调节模型，这将为理解开放新的概念框架 机械负荷如何影响心脏病并有助于确定开发新疗法的分子靶标。