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：每次心跳，心肌细胞都会产生收缩力，将血液泵入循环 心肌细胞还可以感知负荷变化并调整收缩力以维持。 病理状态下的心输出量过多会导致心律失常等心脏病。 然而，心力衰竭的分子和细胞机制仍然存在基础知识空白。 心肌细胞的机械传导以及机械应力相关心脏的治疗 疾病（例如高血压引起的心律失常和心力衰竭、DCM、HFpEF）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很大程度上错过了机械负荷对心肌细胞的影响 我们将开发一种创新的 Cell-in-Gel-TR 技术来控制机械负荷。 我们的研究表明，收缩过程中细胞上的机械负荷可以反馈。 调节兴奋-Ca2+信号传导-收缩（E-C）耦合中的 3 个动态系统； 反馈回路使心肌细胞能够自动调节 E-C 耦合以响应负荷变化。 我们的 R35 研究将探索概念创新，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：我研究的中心主题是阐明。 E-C 中的 3 个动态系统如何耦合前馈和反馈来控制心脏功能 在R35中，我们将在2个R01的基础上扩展和深化我们的研究。 机械传导机制和功能后果的多尺度系统研究 (1)。 分子水平研究破译机械化学电转导 (MCET) 途径，确定关键 (2) 细胞水平研究，研究机械负载如何 调节兴奋-Ca2+信号-收缩耦合的动态系统 (3) 心脏水平研究。 探究机械负荷如何调节完整的心脏功能（4）研究心脏病以了解。 为什么/如何病理性超负荷导致心脏重塑、心律失常和心力衰竭这四个部分是。 旨在相互告知和增强，以提供关于机械传导如何进行的全面视图 通路在分子水平上发挥作用，在细胞水平上整合，并体现在心脏的自动调节能力上 对健康和疾病中机械负荷变化的收缩性：能力和适应性。 我的研究优势源于跨学科方法 我的研究历史显示出强大的优势。 通过结合物理、化学和生物学的严格方法，在新技术方面取得了良好的发展记录。 在R35中，我将继续开发创新的解决方案，并利用尖端技术来实现 变革性的研究目标。预期成果和影响：研究成果将改变范式。 心脏 E-C 与自动调节模型的耦合，这将为理解打开新的概念框架 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。