Genetic analysis of mitochondrial regulators in mammalian cells

描述(由申请人提供)： 这项申请描述了一个为期五年的研究生涯发展计划，研究哺乳动物细胞中线粒体增殖和功能的机制。这项研究计划将在哈佛医学院遗传学教授斯蒂芬·埃利奇博士的实验室进行。埃利奇博士过去成功地培养了许多学术科学家。这位候选人是马萨诸塞州总医院内分泌学、糖尿病和新陈代谢的临床研究员，之前曾与达纳-法伯癌症研究所的布鲁斯·斯皮格尔曼博士一起进行过葡萄糖和脂肪代谢的博士研究。拟议的研究计划将提供遗传方法方面的培训，以分析哺乳动物细胞的调控途径，包括通过RNA干扰实现基因沉默。候选人还将获得一些基因组学和生物信息学方法方面的专业知识。这些经验将补充候选人之前的新陈代谢培训，并将有助于他作为一名独立的内科科学家的发展。为了进一步加强培训，一个由线粒体生物学、新陈代谢和分子生理学以及老鼠遗传学专家组成的咨询委员会将提供科学和职业建议。 在一项利用基于RNAi的遗传筛选的试点研究中，候选人已经确定了一种锌指蛋白作为哺乳动物骨骼肌细胞线粒体生物发生和功能的调节因子。初步证据表明，这种蛋白质在生理环境中受到调控。候选人打算对该蛋白质对肌肉细胞线粒体数量和活性的影响进行进一步的表征。我们将结合生物化学、遗传学和细胞生物学的方法来研究蛋白质作用的分子机制。同时，将进行一个涵盖整个基因组的扩大的RNAi屏幕，以获得调控途径的全球视角，特别强调转录网络。 Elledge实验室提供了激励人心的智力环境、广泛的技术专长和丰富的科学资源，这些都反映了实验室多年来的不断创新。这是一个理想的环境，为候选人的专业发展和成功地开始他的学术生涯作为一名内科科学家。 与公众健康相关(通俗语言)：我们的目标是研究与线粒体增殖和功能有关的基因。这些研究最终可能有助于理解和治疗以线粒体数量和功能异常为特征的疾病，如2型糖尿病。

DESCRIPTION (provided by applicant): This application describes a five-year research career development program in the study of mechanisms of mitochondrial proliferation and function in mammalian cells. The research program will be carried out in the laboratory of Dr. Stephen Elledge, Professor of Genetics at Harvard Medical School. Dr. Elledge has successfully trained many academic scientists in the past. The candidate is a clinical fellow in Endocrinology, Diabetes, and Metabolism at Massachusetts General Hospital, and previously carried out Ph.D. research on glucose and lipid metabolism with Dr. Bruce Spiegelman at Dana-Farber Cancer Institute. The proposed research program will provide training in genetic approaches to analyzing regulatory pathways in mammalian cells, including gene silencing by RNA interference. The candidate will also acquire expertise in a number of genomics and bioinformatics methods. These experiences will complement the candidate's previous training in metabolism and will aid his development as an independent physician-scientist. To further enhance the training, an advisory committee of experts in mitochondrial biology, metabolism and molecular physiology, and mouse genetics will provide scientific and career advice. In a pilot study utilizing an RNAi-based genetic screen, the candidate has identified a zinc finger protein as a regulator of mitochondrial biogenesis and function in mammalian skeletal muscle cells. Preliminary evidence suggests that this protein is regulated in physiological contexts. The candidate intends to carry out further characterization of the effect of the protein on muscle cell mitochondrial number and activity. The molecular mechanism underlying the protein's effect will be investigated using a combination of biochemical, genetic, and cell biological approaches. In parallel, an expanded RNAi screen encompassing the entire genome will be carried out to obtain a global view of the regulatory pathways with particular emphasis on transcriptional networks. The Elledge lab provides a stimulating intellectual environment, broad technical expertise, and extensive scientific resources that reflect years of continuous innovation in the lab. It is an ideal setting for the candidate to develop professionally and to successfully launch his academic career as a physician-scientist. Relevance to public health (lay language): We aim to study the genes involved in mitochondrial proliferation and function. These studies may eventually help understand and treat diseases, such as type 2 diabetes, which are known to be characterized by abnormalities in mitochondrial number and function.