Tissue-specific mitochondrial turnover with aging and energy restriction

描述（由申请人提供）：该候选人是科罗拉多州立大学（CSU）的一名新研究员。候选人的长期目标是获得独立资金，建立一个研究实验室，使用综合和转化的方法来研究能量和蛋白质代谢的相互作用及其在骨骼肌健康衰老中的作用。近期的职业目标是获得一段受保护的研究时间，以开发评估能量变化和衰老的潜在组织特异性线粒体转换的技能。具体而言，拟议的项目解决了蛋白质周转和衰老的线粒体理论，并挑战了蛋白质周转在能量限制（ER）期间增加的范式。该项目将通过冗余测量来检查线粒体周转的短期和长期变化，以完成周转的全面评估。有人提出，线粒体周转的变化将在翻译的步骤中介导，因为翻译是一个能量昂贵的过程。mTOR和PGC-lot通路以及AMPK激活将作为转录和翻译的介质进行探索。目前的提案利用了申请人在稳定同位素示踪剂方面的经验，尽管新的方法将在Marc Hellerstein博士（加州大学伯克利分校，主要顾问）的实验室学习。重要的培训方面将由Greg Cartee博士（密歇根大学，联合导师）和Michael Pagliassotti博士（科罗拉多州立大学，联合导师）指导，包括使用实验动物、ER方法、组织分离技术和细胞信号研究。老年研究的研究设计、监督和专业指导将由Manfred Diehl博士（科罗拉多州立大学，老年研究中心主任，联合导师）提供。

DESCRIPTION (provided by applicant): The candidate is a new investigator at Colorado State University (CSU). The candidate's long-term goal is to obtain independent funding to develop a research laboratory that uses an integrative and translational approach to investigate the interaction of energy and protein metabolism and their roles in the healthy aging of skeletal muscle. The immediate career goal is to obtain a protected period of research to develop skills for the assessment of potential tissue-specific mitochondrial turnover to changes in energy and with aging. Specifically, the proposed project addresses the protein turnover and mitochondrial theories of aging, and challenges the paradigm that protein turnover increases during periods of energy restriction (ER). The project will examine short and long- term changes in mitochondria turnover by redundant measurements to complete a comprehensive assessment of turnover. It is proposed that changes in mitochondria turnover will be mediated at the step of translation, since translation is an energetically expensive process. The mTOR and PGC-lot pathways, as well as AMPK activation will be explored as mediators of transcription and translation. The current proposal exploits the applicant's experience with stable isotopic tracers although new methods will be learned in the laboratory of Dr. Marc Hellerstein (UC-Berkeley, key consultant). Significant training aspects will be directed by Dr. Greg Cartee (University of Michigan, co-mentor) and Dr. Michael Pagliassotti (CSU, co- mentor) with instruction on the use of laboratory animals, ER methodology, tissue isolation techniques, and studies of cellular signaling. Study design, oversight and professional mentorship in aging research will be provided by Dr. Manfred Diehl (CSU, Director of the Center on Aging, co-mentor). RELEVANCE: Mitochondria deterioration has been proposed as causative to age-related decline in function. The current proposal seeks to understand how acute feeding, energy status (energy restricted (ER) or adequately fed), and tissue location effect age-induced changes in mitochondria turnover. It is hoped that the understanding of these processes will aid in safe and effective strategies for successful aging.