Regulation of mitochondrial function by a novel lysine acetyltransferase

新型赖氨酸乙酰转移酶对线粒体功能的调节

• 批准号: 8424515
• 负责人: Iain Scott
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424515
• 关键词: Acetyl Coenzyme A; Acetylation; Acetyltransferase; Affect; Award; Biochemical; Bioenergetics; Biogenesis; Biology; Cell Respiration; Cells; Citric Acid Cycle; Complex; Data; Deacetylase; Deacetylation; Defect; Development; Diabetes Mellitus; Disease; Disease model; Doctor of Philosophy; Electron Transport; Employee Strikes; Environment; Enzymes; Equipment; Event; Extramural Activities; Fatty Acids; Fellowship; Funding; Genetic Screening; Goals; Health; Heart Hypertrophy; Homeostasis; Human; In Vitro; Infection; Intramural Research; Intramural Research Program; K-Series Research Career Programs; Laboratories; Lead; Link; Lysine; Malignant Neoplasms; Mediating; Medical; Mentors; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Proteins; Molecular; Morphology; Mouse-ear Cress; Mus; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; Natural Immunity; Output; Pathway interactions; Physiological; Plant Model; Play; Positioning Attribute; Post-Translational Protein Processing; Power Plants; Presbycusis; Prevention; Protein Acetylation; Proteins; Proteomics; Regulation; Research; Research Personnel; Research Project Grants; Respiration; Role; Scotland; System; Techniques; Testing; Training; United States National Institutes of Health; Work; career; experience; fly; in vivo; mouse model; neuropathology; novel; nutrition; planetary Atmosphere; prevent; protein degradation; reconstitution; research and development; response; tool

DESCRIPTION (provided by applicant): I began my career at the Unversity of St Andrews in Scotland, gaining my Ph.D. in 2006 for research into mitochondrial morphology and dynamics in the model plant Arabidopsis thaliana. On completion of my graduate studies I won a competitive fellowship, giving me the opportunity to experience work in an overseas laboratory. Expanding my horizons, I joined the laboratory of Dr. Richard Youle (NINDS, NIH), where I worked on mitochondrial innate immunity in human and fly cells. In 2009, having enjoyed the switch to a medical-related field, I joined the laboratory of Dr. Michael Sack (NHLBI, NIH). Since joining his research group, I have been investigating the role played by lysine residue acetylation in regulating mitochondrial metabolism. With the support of my mentor, and the exceptional research environment of the NHLBI Divison of Intramural Research, I have been able to make an important step forward in this field. We recently identified the first mitochondrial lysine acetyltransferase (GCN5L1), and showed that it countered the activity of SIRT3 (a lysine deacetylase that was previously the only known regulator of mitochondrial lysine acetylation). We also demonstrated that GCN5L1 regulated mitochondrial respiration and bioenergetic output, indicating that it is an important modulator of mitochondrial metabolism overall. In this K22 Career Development Award application, I propose to use the unique tools available in my mentor's laboratory, and the NHLBI as a whole, to investigate the function of GCN5L1 in mitochondrial metabolism. The NHLBI intramural program provides researchers with excellent facilities (in terms of research space, funding and equipment) and a rich intellectual atmosphere, making it a world-class facility in which to work. During the award I will receive training in proteomics techniques, and then use these to identify both the proteins that are acetylated by GCN5L1, and also the proteins which interact with GCN5L1 to aid its function. With help from my collaborators, both inside and outwith the NHLBI, I will then characterize the function of GCN5L1 in vitro and in vivo. I plan to receive training in mouse handling and safe adenoviral infection techniques, so that I can manipulate GCN5L1 protein levels in mouse models that are relevant to human health. These techniques will be particularly helpful in my goal to investigate the role of GCN5L1 and protein acetylation in mitochondrial turnover. Our initial data suggest that GCN5L1 may be a potent regulator of the systems which control mitochondrial protein degradation, a crucial step in the prevention of multiple disease states. Once my training is complete, I will look to find a research position in the extramural environment, where I can continue to develop this research and begin to build my own laboratory. Once the basic biology of GCN5L1 has been examined, I plan to expand the findings into relevant disease models. The institutional support and superior training available at the NHLBI will be invaluable in the early development of these research plans, and therefore my career as an independent investigator.

描述（由申请人提供）：我的职业生涯始于苏格兰圣安德鲁斯大学，于2006年获得博士学位，研究模式植物拟南芥的线粒体形态和动力学。研究生毕业后，我获得了一份竞争激烈的奖学金，让我有机会在海外实验室体验工作。为了扩大我的视野，我加入了Richard Youle博士（NIH NINDS）的实验室，在那里我研究人类和苍蝇细胞的线粒体先天免疫。2009年，我有幸转到医学相关领域，加入了Michael Sack博士（NHLBI， NIH）的实验室。自从加入他的研究组以来，我一直在研究赖氨酸残基乙酰化在调节线粒体代谢中的作用。在导师的支持下，以及NHLBI校内研究部优越的研究环境，使我在这个领域迈出了重要的一步。我们最近发现了第一个线粒体赖氨酸乙酰转移酶（GCN5L1），并表明它对抗SIRT3（一种赖氨酸去乙酰化酶，以前是线粒体赖氨酸乙酰化的唯一已知调节剂）的活性。我们还证明GCN5L1调节线粒体呼吸和生物能量输出，表明它是线粒体代谢的重要调节剂。在这次K22职业发展奖申请中，我建议使用导师实验室的独特工具，以及NHLBI作为一个整体，来研究GCN5L1在线粒体代谢中的功能。NHLBI的校内项目为研究人员提供了优良的设施（在研究空间、资金和设备方面）和丰富的学术氛围，使其成为世界一流的工作场所。在获奖期间，我将接受蛋白质组学技术的培训，然后使用这些技术来识别被GCN5L1乙酰化的蛋白质，以及与GCN5L1相互作用以帮助其功能的蛋白质。在我的合作者的帮助下，在NHLBI内部和外部，我将在体外和体内表征GCN5L1的功能。我计划接受小鼠处理和安全腺病毒感染技术的培训，以便在与人类健康相关的小鼠模型中操纵GCN5L1蛋白水平。这些技术将特别有助于我研究GCN5L1和蛋白质乙酰化在线粒体周转中的作用。我们的初步数据表明，GCN5L1可能是控制线粒体蛋白降解系统的有效调节剂，这是预防多种疾病状态的关键步骤。一旦我的培训完成，我将寻求在校外环境中找到一个研究职位，在那里我可以继续发展这项研究，并开始建立自己的实验室。一旦研究了GCN5L1的基础生物学，我计划将研究结果扩展到相关的疾病模型中。NHLBI提供的机构支持和优质培训对这些研究计划的早期发展至关重要，因此对我作为一名独立研究者的职业生涯也至关重要。