Cyclophilin D Regulates Neonatal Cardiac Bioenergetics and Function

亲环蛋白 D 调节新生儿心脏生物能和功能

• 批准号: 9815629
• 负责人: George A Porter
• 金额: $ 52.36万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815629
• 关键词: Acetylation; Affect; Bioenergetics; Biological Assay; Biology; Biometry; Birth; Blood Pressure; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Chaperone Protein Inhibition; Congenital Heart Defects; Coupling; Data; Development; Disease; Electron Transport; Embryo; Environment; Equilibrium; Exposure to; Future; Goals; Health; Heart; Human; Hypoxia; In Vitro; Inner mitochondrial membrane; Life; Lung diseases; Measures; Metabolism; Mitochondria; Modeling; Molecular Chaperones; Mus; Muscle Cells; Neonatal; Organelles; Output; Oxygen; Pathology; Pathway interactions; Permeability; Pharmacology; Physiological; Physiology; Play; Process; Production; Proliferating; Proteins; Publishing; Reactive Oxygen Species; Reporting; Role; Specimen; Structure; System; Techniques; Testing; base; clinically relevant; congenital heart disorder; cyclophilin D; experimental study; falls; fatty acid oxidation; genetic approach; heart function; hypoxia neonatorum; in vivo; infection risk; neonatal exposure; neonate; novel; premature; pulmonary function; targeted treatment; uptake

Birth is the most abrupt transition during life, and the neonatal heart must accommodate to this dramatic change in environment by increasing its output to the body. Exposure to higher levels of oxygen at birth likely activates intracellular pathways that allow cardiac myocytes to rapidly proliferate and then differentiate to cause the final maturation of cardiac structure and function that is required for this increased output and survival. However, major gaps in our understanding of this process remain. It is apparent that mitochondria play an important role in this process. We have found that mitochondria regulate cardiac development in the embryo and neonate and that the mitochondrial chaperone protein, cyclophilin D (CyPD), regulates changes in mitochondrial function and reactive oxygen species (ROS) production that control cardiomyocyte proliferation and differentiation. Our preliminary data have begun to define changes in this CyPD-mitochondrial-ROS-differentiation pathway that occur in the neonatal heart. In addition, these data provide novel models to dissect the mechanisms of this pathway. These findings suggest the hypothesis that increased O2 at birth initiates a rise and then fall in CyPD activity, which regulates mitochondrial function, particularly ROS production, to control neonatal myocyte proliferation and differentiation and cardiac function. The scientific premise of this proposal is supported by data discussed above, but the mechanisms involved have not been fully elucidated. Our overall goal is to use our expertise in cardiac development and mitochondrial biology to dissect the mechanisms that control this important physiologic pathway in the neonatal heart and determine if CyPD inhibition can be used to ameliorate pathology in clinically relevant models. To achieve these goals, we propose 3 Specific Aims: 1. Determine how CyPD controls the neonatal cardiac mitochondrial-ROS-differentiation pathway. 2. Determine effects of disrupting CyPD activity in the neonatal heart. 3. Determine effects of hypoxia on the neonatal CyPD- mitochondria-ROS-differentiation pathway. The proposed experiments use a novel set of pharmacologic and genetic approaches that manipulate oxygen, CyPD, inner mitochondrial membrane coupling, and ROS in the neonatal heart. Specimens will be processed using a battery of assays to measure CyPD expression, acetylation, and activity; mitochondrial structure and function, ETC activity and assembly, ROS production; myocyte proliferation and differentiation; and cardiac function. Our team has unique expertise in cardiac, developmental, and mitochondrial biology and in biostatistics and we employ novel concepts and cutting-edge techniques to study mitochondria during late cardiac development. The anticipated results will significantly change our understanding of bioenergetics in the neonatal heart and will lead to future studies that use mitochondrial targeted therapies to enhance cardiac function and cardiac myocyte differentiation in a variety of disease states in the neonatal and mature heart.

出生是生命中最突然的转变，新生儿的心脏必须适应这种戏剧性的变化。 通过增加其对身体的输出来改变环境。出生时暴露在高浓度的氧气中 激活细胞内通路，使心肌细胞迅速增殖，然后分化为 导致心脏结构和功能的最终成熟，这是增加输出所必需的， 生存然而，我们对这一进程的理解仍然存在重大差距。 很明显，线粒体在这一过程中起着重要作用。我们发现线粒体 调节胚胎和新生儿的心脏发育，线粒体伴侣蛋白， 亲环素D（CyPD）调节线粒体功能和活性氧（ROS）的变化 生产控制心肌细胞增殖和分化。我们的初步数据已经开始 定义在新生儿心脏中发生的CyPD-线粒体-ROS-分化途径的变化。在 此外，这些数据提供了新的模型来剖析这一途径的机制。 这些发现表明，出生时增加O2会引发CyPD升高，然后下降的假设 活性，调节线粒体功能，特别是ROS的产生，以控制新生心肌细胞 增殖和分化以及心脏功能。这一建议的科学前提得到以下方面的支持： 数据，但所涉及的机制尚未完全阐明。我们的总体目标是利用 我们在心脏发育和线粒体生物学方面的专业知识， 新生儿心脏中重要的生理途径，并确定CyPD抑制是否可用于 改善临床相关模型中的病理学。为了实现这些目标，我们提出了三个具体目标：1。 确定CyPD如何控制新生儿心肌细胞-ROS-分化途径。2.确定 破坏新生儿心脏中CyPD活性的影响。3.确定缺氧对新生儿CyPD的影响- α-ROS-分化途径。 拟议的实验使用了一套新的药理学和遗传学方法， 新生儿心脏中的氧、CyPD、线粒体内膜偶联和ROS。标本将 使用一系列测定法处理以测量CyPD表达、乙酰化和活性;线粒体 结构与功能、ETC活性与组装、ROS产生、肌细胞增殖与分化; 和心脏功能。我们的团队在心脏、发育和线粒体生物学方面拥有独特的专业知识， 在生物统计学中，我们采用新概念和尖端技术来研究晚期线粒体 心脏发育预期的结果将大大改变我们对生物能量学的理解， 新生儿心脏，并将导致未来的研究，使用线粒体靶向治疗，以提高心脏 功能和心肌细胞分化在新生儿和成熟心脏的各种疾病状态。