Genetic analysis of mitochondrial regulators in mammalian cells

哺乳动物细胞线粒体调节因子的遗传分析

基本信息

批准号：
8281494
负责人：
JOHN C YOON
金额：
$ 16.02万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8281494
关键词：
Advisory Committees Affect Animal Model Biochemical Biochemical Genetics Biogenesis Bioinformatics Biological Biological Assay Biology Cell Line Cells Clinical Complement Congenital Abnormality Dana-Farber Cancer Institute Data Degenerative Disorder Development Diabetes Mellitus Disease Doctor of Philosophy Endocrinology Energy Metabolism Environment Exercise Gene Expression Gene Expression Profiling Gene Silencing Gene Targeting General Hospitals Generations Genes Genetic Genetic Screening Genome Genomic Library Genomics Human Individual Insulin Resistance Investigation Laboratories Language Link Mammalian Cell Massachusetts Membrane Potentials Metabolic Diseases Metabolism Methods Mitochondria Molecular Morphology Mus Muscle Muscle Cells Muscle Fibers Mutation Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Oxygen Consumption Pathology Phenotype Physicians Physiological Physiology Pilot Projects Play Process Production Protein Binding Proteins Public Health RNA Interference Regulation Regulatory Pathway Reporter Genes Research Research Personnel Resources Respiration Role Scientist Screening procedure Signal Pathway Skeletal Muscle Small Interfering RNA Structure Syndrome Technical Expertise Techniques Testing Training Transcriptional Activation Transfection Zinc Fingers base career career development density experience gene repression genetic analysis glucose metabolism high throughput screening in vivo innovation insight lipid metabolism loss of function medical schools mitochondrial dysfunction mitochondrial membrane mouse genome overexpression professor programs promoter protein expression research study scale up tool

项目摘要

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.

描述（由申请人提供）：该申请描述了一项为期五年的研究职业发展计划，研究哺乳动物细胞中线粒体增殖和功能的机制。该研究计划将在哈佛医学院遗传学教授 Stephen Elledge 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。该候选人是马萨诸塞州总医院内分泌学、糖尿病和代谢学的临床研究员，此前曾获得博士学位。与 Dana-Farber 癌症研究所的 Bruce Spiegelman 博士一起研究葡萄糖和脂质代谢。拟议的研究计划将提供遗传方法培训，以分析哺乳动物细胞的调控途径，包括通过 RNA 干扰进行基因沉默。候选人还将获得许多基因组学和生物信息学方法的专业知识。这些经验将补充候选人之前在新陈代谢方面的培训，并有助于他作为一名独立的医师科学家的发展。为了进一步加强培训，由线粒体生物学、新陈代谢和分子生理学以及小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，候选人已确定锌指蛋白是哺乳动物骨骼肌细胞中线粒体生物发生和功能的调节剂。初步证据表明该蛋白质在生理环境中受到调节。该候选人打算进一步表征该蛋白质对肌肉细胞线粒体数量和活性的影响。将结合生化、遗传和细胞生物学方法来研究蛋白质作用的分子机制。与此同时，将进行涵盖整个基因组的扩展 RNAi 筛选，以获得调控途径的全局视图，特别强调转录网络。 Elledge 实验室提供了令人兴奋的智力环境、广泛的技术专业知识和广泛的科学资源，反映了实验室多年来的持续创新。对于候选人的专业发展和成功开展其作为医师科学家的学术生涯来说，这是一个理想的环境。与公共卫生的相关性（外行语言）：我们的目标是研究参与线粒体增殖和功能的基因。这些研究最终可能有助于理解和治疗疾病，例如 2 型糖尿病，已知这些疾病的特点是线粒体数量和功能异常。