Mitophagy as a regulator of cardiac function in physiological and pathophysiological conditions

线粒体自噬作为生理和病理生理条件下心脏功能的调节剂

• 批准号: 9762156
• 负责人: Nuo Sun
• 金额: $ 24.59万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762156
• 关键词: Adult; Advisory Committees; Attenuated; Award; Brain; Cardiac; Cardiac Function Study; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular Physiology; Cause of Death; Communication; Complement; Data; Deubiquitinating Enzyme; Development; Development Plans; Disease; Down-Regulation; Educational process of instructing; Educational workshop; Embryo; Energy Metabolism; Energy-Generating Resources; Enzymes; Excision; Extramural Activities; Fatty Acids; Functional disorder; Funding; Genetic; Glucose; Goals; Grant; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; In Vitro; Intramural Research Program; K-Series Research Career Programs; K22 Award; Knockout Mice; Knowledge; Leadership; Life; Link; Measures; Mediating; Membrane Proteins; Mentors; Metabolic; Mitochondria; Modeling; Mus; Myocardial dysfunction; National Heart, Lung, and Blood Institute; Nerve Degeneration; Outer Mitochondrial Membrane; Pathologic; Pathway interactions; Perinatal; Pharmacology; Phase; Physiological; Physiology; Play; Preparation; Program Development; Protein Isoforms; Proteomics; Public Health; Quality Control; Regulation; Reporter; Research; Research Personnel; Research Proposals; Research Training; Role; Scientist; Stress; Techniques; Testing; Therapeutic; Tissues; Training; Ubiquitin-Conjugating Enzymes; United States National Institutes of Health; Vocational Guidance; Work; Writing; body system; cardiogenesis; career; career development; constriction; design; fatty acid oxidation; fetal; heart function; heart preservation; in vivo; in vivo monitoring; inhibitor/antagonist; innovation; insight; meetings; member; mitochondrial autophagy; mitochondrial dysfunction; mitochondrial metabolism; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; oxidation; parkin gene/protein; perinatal period; post-doctoral training; pressure; prevent; programs; research and development; response; skills; success

7. Project Summary Mitochondria provide an essential source of energy and play an important role during cardiac development and in heart failure progression. Cumulative evidence illustrates the importance of mitochondrial quality control in cardiac function during fetal life and in the adult heart. This K22 application centers on a research proposal to study the role of cardiac mitophagy, an important aspect of mitochondrial quality control, in both physiological and pathophysiological conditions within the context of a career development program. The program is designed to facilitate a successful transition from postdoctoral training to independent research. These studies will be facilitated by my recently described mt-Keima mouse model to monitor in vivo cardiac mitophagic flux, as well as the use of genetic Parkin deficient (a positive mitophagy regulator) and USP30 deficient (a negative mitophagy regulator) mouse models. This will be supplemented by detailed cardiac functional analysis using murine models of transverse aortic constriction induced cardiomyopathy. In particular, I will determine the role of mitophagy in perinatal cardiac mitochondrial maturation and during cardiac pathological stresses, as well as test a specific USP30 inhibitor in stimulating cardiac mitophagy and in attenuating progression of heart failure (Aim 1). It is increasingly recognized that mitophagy is critical for mitochondrial plasticity and metabolic reprogramming during normal heart development and in various disease conditions. I will further test the hypothesis that the rate limiting enzyme in fatty acid oxidation, CPT1a, may regulate mitophagy. Using a cardiac specific CPT1a knockout mouse, I will assess whether CPT1a regulates the mitochondrial perinatal metabolic transition and the adult mitophagic response that occurs following cardiac stress (Aim 2). Completion of the proposed Research Strategy will produce critical insights into the role of mitophagy in normal cardiovascular physiology and pathological conditions, and will fundamentally advance our understanding of the interaction between mitochondrial metabolism and mitochondrial quality control in the heart. This enhanced understanding of the role of mitophagy, USP30 and CPT1a in the heart should open possibilities for harnessing these pathways for therapeutic potential. These studies will be initiated within the NIH intramural program and completed during an extramural, independent phase. Through this K22 Career Development Award proposal, I seek to systematically acquire additional mentored research training and career development training at the NIH/NHLBI through a detailed Career Development Plan designed to complement my current skill set, including additional formal training in cardiac physiology and pathophysiology. With the continued support of members of my Advisory Committee, the K22 Career Development Award will establish a training framework to initiate the research program in preparation for my independent career. A central part of the intramural phase of the K22 award will be my Advisory Committee that will evaluate my progress on the proposed research and career development training as outlined in the detailed Career Development Plan. The advisory committee composed of intramural and extramural members will provide continuous guidance. The scientific training will support the proposed Specific Aims through a combination of specialized course work and hands-on training to complete the proposed innovative Research Strategy. Importantly, the techniques and approaches developed during the funding period of the award will not only advance our understanding of physiological role of cardiac mitophagy, but also allow for the successful completion of the proposed Research Strategy. This will establish the basis of my first NIH R01 and additional independent funding applications. I will also undertake extensive career and professional training in the intramural phase of this award to help master academic challenges anticipated in the extramural phase of the award. Mentoring and teaching will be complemented with training in management and leadership in the form of seminars and workshops. The professional career development training also involves mentoring of junior scientists, participation in grant- writing workshops, development of communication skills, networking at meetings, career counseling and assessment coaching to prepare for my transition to independence and my long term goal of becoming a successful independent investigator. Cardiovascular disease represents the leading cause of death in the USA, understanding the mechanisms regulating cardiac mitophagy that protect the heart from heart failure and cardiac hypertrophy could prove invaluable to public health. Constitutive mitophagy is a homeostatic mechanism for maintaining mitochondrial quality and global mitochondrial function not only in the heart, but also in other tissues. As my career develops, I envision that I will use the insight I have gained from studying the function of cardiac mitophagy and apply this knowledge to investigate the role of mitophagy in a variety of contexts in other organs and systems, particularly in the brain, where I have demonstrated an important role of mitophagy in neuronal degeneration. In summary, the proposed studies will illustrate the importance of mitophagy in the perinatal and adult heart. These insights may provide the basis for novel therapeutic approaches in a wide variety of heart diseases. In addition, the described career development plan will notably enhance my transition to academic independence and chances for continued scientific success.

七、项目概要 线粒体提供重要的能量来源，在心脏发育过程中发挥重要作用 以及心力衰竭的进展。累积证据说明线粒体质量控制的重要性 影响胎儿时期和成人心脏的心脏功能。此 K22 申请以一项研究计划为中心 研究心脏线粒体自噬（线粒体质量控制的一个重要方面）在这两种疾病中的作用 职业发展计划背景下的生理和病理生理条件。这 该计划旨在促进从博士后培训到独立研究的成功过渡。 我最近描述的 mt-Keima 小鼠模型将促进这些研究，以监测体内心脏 线粒体自噬通量，以及使用遗传 Parkin 缺陷（正线粒体自噬调节因子）和 USP30 缺陷（负线粒体自噬调节因子）小鼠模型。这将得到详细的心脏信息的补充 使用横向主动脉缩窄诱发的心肌病小鼠模型进行功能分析。尤其， 我将确定线粒体自噬在围产期心脏线粒体成熟和心脏过程中的作用 病理应激，以及测试特定的 USP30 抑制剂刺激心脏线粒体自噬和 减缓心力衰竭的进展（目标 1）。人们越来越认识到线粒体自噬对于 正常心脏发育和各种疾病期间的线粒体可塑性和代谢重编程 状况。我将进一步检验脂肪酸氧化中的限速酶 CPT1a 的假设 调节线粒体自噬。使用心脏特异性 CPT1a 敲除小鼠，我将评估 CPT1a 是否调节 线粒体围产期代谢转变和成年后发生的线粒体自噬反应 压力（目标 2）。完成拟议的研究战略将对以下方面的作用产生重要的见解： 线粒体自噬在正常心血管生理和病理条件下的作用，将从根本上促进 我们对线粒体代谢和线粒体质量控制之间相互作用的理解 心。这增强了人们对线粒体自噬、USP30 和 CPT1a 在心脏中的作用的理解。 利用这些途径发挥治疗潜力的可能性。这些研究将在 NIH 校内项目并在校外独立阶段完成。 通过这个 K22 职业发展奖提案，我寻求系统地获得更多 通过详细的职业指导，在 NIH/NHLBI 进行研究培训和职业发展培训 旨在补充我当前技能的发展计划，包括额外的心脏方面的正式培训 生理学和病理生理学。在我的咨询委员会成员的持续支持下，K22 职业发展奖将建立一个培训框架，以启动准备中的研究计划 为了我的独立事业。 K22 奖校内阶段的核心部分将是我的咨询 委员会将评估我在拟议的研究和职业发展培训方面的进展 详细的职业发展计划中有概述。咨询委员会由校内和 校外成员将提供持续指导。科学培训将支持拟议的具体 旨在通过专业课程工作和实践培训相结合来完成建议的 创新的研究策略。重要的是，融资期间开发的技术和方法 获奖期间不仅将增进我们对心脏线粒体自噬的生理作用的理解，而且 允许成功完成拟议的研究战略。这将为我的第一个项目奠定基础 NIH R01 和其他独立资助申请。 我还将在该奖项的校内阶段进行广泛的职业和专业培训，以帮助 掌握奖项校外阶段预期的学术挑战。指导和教学将 并以研讨会和讲习班的形式进行管理和领导力培训。这 专业职业发展培训还包括对初级科学家的指导、参与资助项目 写作研讨会、沟通技巧发展、会议网络、职业咨询和 评估辅导，为我向独立的过渡和成为一名独立人士的长期目标做准备 成功的独立调查员。 心血管疾病是美国的首要死因，了解其机制 调节心脏线粒体自噬以保护心脏免受心力衰竭和心脏肥大的影响可能会被证明 对公共卫生来说是无价的。组成型线粒体自噬是维持线粒体功能的稳态机制 质量和整体线粒体功能不仅在心脏中，而且在其他组织中。随着我职业生涯的发展， 我设想我将利用从研究心脏线粒体自噬功能中获得的见解并将其应用 研究线粒体自噬在其他器官和系统的各种情况下的作用的知识，特别是 在大脑中，我证明了线粒体自噬在神经元变性中的重要作用。总之， 拟议的研究将说明线粒体自噬在围产期和成人心脏中的重要性。这些见解 可能为多种心脏病的新治疗方法提供基础。此外， 所述职业发展计划将显着增强我向学术独立的过渡和机会 为了持续的科学成功。