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.

7。项目摘要 线粒体提供了必不可少的能源，并在心脏发展中起重要作用 并在心力衰竭进展中。累积证据说明了线粒体质量控制的重要性 在胎儿生活和成人心脏中的心脏功能中。该K22应用程序以研究建议为中心 研究心脏线粒体的作用，这是线粒体质量控制的重要方面 在职业发展计划的背景下，生理和病理生理状况。这 计划旨在促进从博士后培训到独立研究的成功过渡。 这些研究将由我最近描述的MT-Keima小鼠模型促进，以监测体内心脏 线粒体通量，以及遗传帕克蛋白缺乏（阳性线粒体调节剂）和USP30的使用 缺乏线粒体调节器）小鼠模型。这将通过详细的心脏补充 使用横向主动脉收缩诱导心肌病的鼠模型的功能分析。尤其， 我将确定线粒体在围产期心脏线粒体成熟和心脏中的作用 病理应力，并测试特定的USP30抑制剂在刺激心脏线索和中 减轻心力衰竭进展（目标1）。越来越认识到线粒体对 正常心脏发育和各种疾病中的线粒体可塑性和代谢重编程 状况。我将进一步检验以下假设，即限制脂肪酸氧化中的酶，CPT1A，可能 调节线粒体。使用心脏特异性CPT1A敲除鼠标，我将评估CPT1A是否调节 线粒体围产期代谢过渡和心脏后发生的成年线粒体反应 压力（目标2）。拟议的研究策略的完成将产生对角色的重要见解 正常心血管生理和病理状况的线粒体，从根本上可以进步 我们对线粒体代谢与线粒体质量控制之间的相互作用的理解 心。对线粒体，USP30和CPT1A在心脏中的作用的增强理解应开放 利用这些途径以获得治疗潜力的可能性。这些研究将在 NIH壁内计划，并在壁外独立阶段完成。 通过这项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，在NIH/NHLBI的指导研究培训和职业发展培训 开发计划旨在补充我当前的技能，包括心脏的其他正式培训 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，以启动研究计划进行准备 对于我的独立职业。我的建议将是K22奖的壁内阶段的中心部分 委员会将评估我在拟议的研究和职业发展培训上的进步 在详细的职业发展计划中概述。由壁内和 壁外成员将提供持续的指导。科学培训将支持拟议的特定 通过专门的课程工作和动手培训的结合来完成建议 创新研究策略。重要的是，资金期间开发的技术和方法 奖励期间不仅会提高我们对心脏线索生理作用的理解，而且还会提高我们的理解 允许成功完成拟议的研究策略。这将建立我的第一个基础 NIH R01和其他独立资金申请。 我还将在该奖项的壁内阶段接受广泛的职业和专业培训，以帮助 奖项的校园外阶段所期望的主要学术挑战。指导和教学将是 以研讨会和研讨会的形式接受管理和领导培训的培训。这 职业职业发展培训还涉及指导初级科学家，参与赠款 - 编写研讨会，沟通技巧的发展，会议上的网络，职业咨询和 评估教练为我的过渡到独立和我成为一个的长期目标做准备 成功的独立研究员。 心血管疾病是美国死亡的主要原因，了解机制 调节保护心脏免受心力衰竭和心脏肥大的心脏线粒体可能证明 对公共卫生的宝贵。构成线粒体是维持线粒体的稳态机制 质量和全球线粒体功能不仅在心脏中，而且在其他组织中。随着我的职业发展， 我设想我将利用我从研究心脏线索功能中获得的见解并应用此 知识以研究线粒体在其他器官和系统中的各种情况下的作用，尤其是 在大脑中，我在神经元变性中表现出了线粒体的重要作用。总之， 拟议的研究将说明线粒体在围产期和成人心脏中的重要性。这些见解 可以为各种心脏病的新型治疗方法提供基础。另外， 描述的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。