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）：我在苏格兰圣安德鲁斯大学开始了我的职业生涯，获得了我的博士学位。2006年，他在模式植物拟南芥中进行了线粒体形态学和动力学的研究。在完成研究生学业后，我获得了一个竞争性的奖学金，使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（NINDS，NIH）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，我很高兴地转到了医学相关领域，加入了Michael Sack博士的实验室（NHLBI，NIH）。自从加入他的研究小组以来，我一直在研究赖氨酸残基乙酰化在调节线粒体代谢中所起的作用。在我的导师的支持下，以及NHLBI校内研究部的特殊研究环境，我已经能够在这一领域迈出重要的一步。我们最近发现了第一个线粒体赖氨酸乙酰转移酶（GCN 5L1），并表明它对抗SIRT 3（一种赖氨酸脱乙酰酶，以前是线粒体赖氨酸乙酰化的唯一已知调节剂）的活性。我们还证明了GCN 5L1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K22职业发展奖申请中，我建议使用我导师实验室和整个NHLBI中可用的独特工具来研究GCN 5L1在线粒体代谢中的功能。NHLBI内部计划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设施。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鉴定被GCN 5L1乙酰化的蛋白质，以及与GCN 5L1相互作用以帮助其功能的蛋白质。在NHLBI内外合作者的帮助下，我将在体外和体内表征GCN 5L1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，这样我就可以操纵与人类健康相关的小鼠模型中的GCN 5L1蛋白水平。这些技术将特别有助于我研究GCN 5L1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，GCN 5L1可能是控制线粒体蛋白质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，我将寻找一个研究职位，在校外环境，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GCN 5L1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提供的机构支持和上级培训将在这些研究计划的早期发展中发挥不可估量的作用，因此，我作为一名独立研究者的职业生涯也是如此。