Core D: Comparative Mitochondrial Health Assessment Core

核心 D：比较线粒体健康评估核心

• 批准号: 8958641
• 负责人: VICTOR M DARLEY-USMAR
• 金额: $ 11.3万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8958641
• 关键词: Adipose tissue; Age; Aging; Aging-Related Process; Area; Autophagocytosis; Bioenergetics; Biology; Birds; Body Size; Cells; Cellular Structures; Chronic; Chronic Disease; Communities; Complement; Complex; Consultations; Cryopreserved Cell; DNA; DNA Sequence; Data; Deterioration; Development; Educational workshop; Electrodes; Experimental Designs; Fibroblasts; Fishes; Functional disorder; Funding; Genetic; Goals; Grant; Health; Islets of Langerhans; Life; Longevity; Maintenance; Mammals; Mass Spectrum Analysis; Measurement; Measures; Metabolic; Metabolic stress; Metabolism; Methods; Mitochondria; Mitochondrial DNA; Mitotic; Modeling; Molecular; Monitor; Mus; Nerve Degeneration; Nuclear; Organelles; Organism; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathogenesis; Process; Proteins; Protocols documentation; Quality Control; Research; Research Personnel; Resistance; Role; Services; Stress; Sulfhydryl Compounds; Surveys; Techniques; Technology; Testing; Tissue Sample; Tissues; Training; Training and Education; Translational Research; Yeasts; age related; base; comparative; extracellular; fly; healthy aging; indexing; inhibition of autophagy; interest; member; metabolomics; mitochondrial autophagy; mitochondrial dysfunction; novel; oxidized lipid; programs; protein aggregate; research study; response; virtual

The maintenance of normal mitochondrial function varies between organisms as does their oxygen metabolism and response to pathophysiological stress. Although bioenergetic metrics have been surveyed in a broad range of aging models these parameters have yet to be integrated with measures of the control of mitochondrial quality and mitochondrial genetics. We have introduced the concept of Bioenergetic health in translational research and now plan to extend this to models of aging. In the Comparative Mitochondrial Health Assessment core both state of the art and established techniques in bioenergetics, mitochondrial genetics, autophagy and redox biology will be offered. The mechanisms controlling mitochondrial health involve mitochondrial genetics, mitochondrial-nuclear interaction and mitophagy. The novel models offered to the aging community will be the mitochondrial nuclear exchange (MNX) mice which have been pioneered at UAB. This allows the contribution of specific mitochondrial DNA sequences to the process of aging to be assessed independent of the nuclear contribution. State of the art experimental design, and protocols for assessing cellular bioenergetics in response to oxidative and metabolic stress will also be used. As autophagy and mitophagy have been shown to be essential for healthy lifespan, and insufficient autophagy contributes to accumulation of protein aggregates and dysfunctional mitochondria, indices of autophagic flux can be measured. An important aspect of the Core is extending these techniques to a variety of traditional species from yeast to mice, including both cryopreserved “cell zoo” of fibroblasts from about 60 species of mammals and birds, a lot of these from species of “exceptional biogerontological interest”, as well as live species that are either exceptionally long-lived or short-lived for their body size, such as the short-lived fish, Nothobranchius furzeri. Specifically, services will be provided to NIA Regular and Supported Members and pilot & feasibility grant awardees in: 1. Molecular energetics analysis including cellular, organelle and tissue measurements, including approaches we have pioneered in spheroid like cell structures and complex multi-cellular structures such as pancreatic islets, vessel segments and adipose tissue, and complementing approaches with targeted metabolomics and oxygen electrodes. 2. Quantitative oxidative stress parameters to assess indices of redox changes including oxidized lipids, thiols and modified proteins. 3. Mitochondrial nuclear exchange (MNX) models, mtDNA damage and haplotyping to test the unique contribution of mtDNA sequences to bioenergetics and the resistance to metabolic and oxidative stress, with approaches available for both the traditional murine models and comparative models of aging used throughout the Center. 4. Autophagy and mitophagy assessments in the context of the pathobiology of oxidative stress and neurodegeneration will be extended to the models of aging. 5. Virtual and wet lab workshop educational programs.

正常线粒体功能的维持因生物体而异，其氧代谢也是如此 和对病理生理应激的反应。虽然生物能量指标已经在广泛的调查， 这些参数尚未与控制老化的措施相结合， 线粒体质量和线粒体遗传学。我们已经引入了生物能量健康的概念， 转化研究，现在计划将其扩展到衰老模型。比较线粒体 健康评估的核心是生物能量学、线粒体、 将提供遗传学、自噬和氧化还原生物学。控制线粒体健康的机制 涉及线粒体遗传学、细胞核相互作用和线粒体自噬。新的模型提供给 衰老群体将是线粒体核交换（MNX）小鼠， UAB。这使得特定的线粒体DNA序列对衰老过程的贡献被认为是可能的。 与核贡献无关。最先进的实验设计和方案， 还将使用评估响应于氧化和代谢应激的细胞生物能量学。作为自噬 和线粒体自噬已被证明是健康寿命所必需的，而自噬不足有助于 蛋白质聚集体的积累和功能障碍的线粒体，自噬通量的指数可以被 测定了核心的一个重要方面是将这些技术扩展到各种传统物种 从酵母到小鼠，包括来自约60种哺乳动物的成纤维细胞的冷冻保存的“细胞动物园”， 和鸟类，其中很多来自“特殊的生物学兴趣”的物种，以及活的物种， 无论是非常长寿或短命的身体大小，如短命鱼，假鳃鱼 furzeri。具体而言，将向NIA常规和支持会员提供服务，并进行试点和可行性研究。 授予获奖者：1.分子能量学分析，包括细胞、细胞器和组织测量， 包括我们在球状细胞结构和复杂的多细胞结构方面开创的方法 如胰岛、血管段和脂肪组织，以及补充靶向 代谢组学和氧电极。2.用于评估氧化还原指数的定量氧化应激参数 包括氧化脂质、硫醇和修饰蛋白质的变化。3.线粒体核交换 模型，mtDNA损伤和单体型分析，以测试mtDNA序列对生物能量学的独特贡献 以及对代谢和氧化应激的抵抗力，这些方法既适用于传统的小鼠， 模型和老化的比较模型在整个中心使用。4.自噬和线粒体自噬 在氧化应激和神经变性的病理生物学背景下的评估将扩展到 衰老的模型。5.虚拟和湿实验室研讨会教育计划。