Regulation of mitochondrial function by a novel lysine acetyltransferase

简介(申请人提供)：我的职业生涯始于苏格兰圣安德鲁斯大学，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，这让我有机会体验在海外实验室的工作。扩大了我的视野，我加入了理查德·尤勒博士(NINDS，NIH)的实验室，在那里我致力于人类和飞行细胞的线粒体先天免疫。2009年，在享受了转到与医学相关的领域后，我加入了迈克尔萨克博士(NHLBI，NIH)的实验室。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。在我导师的支持下，以及NHLBI校内研究部特殊的研究环境下，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)，并表明它与SIRT3的活性相反(SIRT3是一种赖氨酸脱乙酰酶，以前是线粒体赖氨酸乙酰化的唯一调节因子)。我们还证明了GCN5L1调节线粒体呼吸和生物能量输出，表明它是线粒体整体代谢的重要调节器。在这份K22职业发展奖的申请中，我建议使用我导师的实验室和NHLBI作为一个整体提供的独特工具来研究GCN5L1在线粒体代谢中的功能。NHLBI校内项目为研究人员提供了一流的设施(在研究空间、资金和设备方面)和丰富的智力氛围，使其成为世界级的工作设施。在获奖期间，我将接受蛋白质组学技术方面的培训，然后使用这些技术来鉴定被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NHLBI内外合作者的帮助下，我将在体外和体内表征GCN5L1的功能。我计划接受老鼠操作和安全的腺病毒感染技术方面的培训，这样我就可以操纵与人类健康相关的小鼠模型中的GCN5L1蛋白水平。这些技术将特别有助于我的目标，即研究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质降解的系统的有效调节因子，线粒体蛋白质降解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，在那里我可以继续开展这项研究，并开始建立自己的实验室。一旦GCN5L1的基本生物学研究完成，我计划将这一发现扩展到相关的疾病模型中。NHLBI提供的机构支持和高级培训对这些研究计划的早期发展将是无价的，因此我作为一名独立调查员的职业生涯也将是无价的。

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.