Obesity and diabetes genetics in Caenorhabditis elegans.

秀丽隐杆线虫的肥胖和糖尿病遗传学。

• 批准号: 8066937
• 负责人: ALEXANDER A SOUKAS
• 金额: $ 16.02万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066937
• 关键词: Advisory Committees; Affect; Animals; Area; Award; BODIPY; Biochemical; Biochemical Pathway; Biochemistry; Biological Assay; Biological Phenomena; Biology; Body Size; Body fat; C. elegans genome; CCL4 gene; Caenorhabditis elegans; Candidate Disease Gene; Cessation of life; Complex; Cost of Illness; Databases; Defect; Dependence; Development; Diabetes Mellitus; Disease; Doctor of Medicine; Doctor of Philosophy; Dyes; Electrophoresis; Environment; Essential Genes; Faculty; Fatty Acids; Fatty acid glycerol esters; Five-Year Plans; Funding; Fusion Protein Expression; Future; General Hospitals; Genes; Genetic; Genetic Models; Genetic Screening; Genome; Genomics; Glucocorticoids; Goals; Gold; Growth; Homeostasis; Human; Human Genetics; Image Analysis; Immunoprecipitation; Insulin; Investigation; K-Series Research Career Programs; Label; Laboratories; Learning; Lipids; Longevity; Lysosomes; Maps; Mass Fragmentography; Mass Spectrum Analysis; Massachusetts; Mediating; Medicine; Mentors; Mentorship; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Methods; Microscopy; Mitochondria; Molecular; Molecular Biology; Mutagenesis; Mutate; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Organ; Organism; Pathogenesis; Pathway interactions; Phenocopy; Phenotype; Phosphopeptides; Phosphotransferases; Physicians; Play; Positioning Attribute; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Quantitative Microscopy; RNA Interference; Reagent; Regulation; Regulator Genes; Reporter; Reproduction; Research; Research Personnel; Research Training; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; Scientist; Serum; Signal Transduction; Silver Staining; Sirolimus; Societies; Staining method; Stains; System; Techniques; Technology; Time; Tissues; Training; Transgenes; Transgenic Organisms; Triglycerides; Western Blotting; Whole Organism; Work; career; career development; combat; cost; design; diabetes mellitus genetics; functional genomics; gain of function; gene discovery; genome sequencing; high throughput technology; improved; inorganic phosphate; instructor; lipid metabolism; medical schools; mouse model; mutant; new technology; next generation; nile red; oil red O; overexpression; premature; professor; programs; promoter; public health relevance; reproductive; years of life lost

DESCRIPTION (provided by applicant): This proposal describes a five year plan for Alexander Soukas to transition to an independently-funded investigator with expertise in functional genomics of obesity and diabetes. Dr. Soukas, an instructor in medicine and assistant in molecular biology at Massachusetts General Hospital, will be mentored by Gary Ruvkun, Ph.D., professor of genetics at Harvard Medical School. Dr. Ruvkun is a worldwide expert in C. elegans biology, metabolism, genetics, and genomics, a Lasker Award winner, and has a very strong record of mentorship, having supervised 38 trainees, 24 of which have academic, tenure-track faculty positions. An advisory committee of physician-scientists with expertise in human genetics, lipid metabolism, cell signaling, and mitochondrial biology made up of David Altshuler, M.D., Ph.D., Joseph Avruch, M.D., Mason Freeman, M.D., and Vamsi Mootha, M.D. will provide scientific direction, ground the investigator in medically-relevant lines of research, and provide career guidance during the transition to independent investigator. Dr. Soukas will carry out the planned career development activities in the research and training environment at the Massachusetts General Hospital and Harvard Medical School. The research program proposes use of the organism C. elegans to identify candidate genes involved in the pathogenesis of obesity and diabetes. Obesity and type 2 diabetes are extremely prevalent, highly associated diseases that cost the US more than $174 billion in 2007, and produce an even greater cost on society in terms of life-years lost. Given the tremendous conservation in ancient pathways regulating energy homeostasis, we hypothesize that identification of conserved genes regulating fat in C. elegans will illuminate human genetic pathways regulating energy homeostasis, and possibly even obesity and diabetes disease mechanisms. Preliminary studies on C. elegans have isolated more than 50 mutants with altered fat content. Those most notable identified to date are the conserved genes rictor, an essential component of target of rapamycin complex 2 (TORC2) protein kinase, and serum and glucocorticoid-induced kinase (sgk-1), an Akt-related kinase that acts downstream of TORC2. Completed studies of C. elegans rictor indicate that it is a central regulator of metabolism, controlling fat mass, growth, reproduction, and lifespan through regulation of the kinases AKT and SGK4. The investigator will learn to apply genomics (RNA interference, whole-genome sequencing, high-throughput technology), forward genetics, and biochemistry 1) to identify new mutations in genes that alter C. elegans fat content, 2) to determine the cellular and molecular mechanism by which altered fat mass is generated in rictor/TORC2 and other mutants, and 3) build a network of genetic interactions regulating body fat. The ultimate goals of this work are to identify and characterize genes that play a conserved role in energy homeostasis in C. elegans and humans, to inform human genetic and mouse model studies of obesity and diabetes, and to transition to independent investigator status. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes are associated diseases well recognized to be among the leading causes of premature illness and death. This career development award proposes training to establish the applicant as an independent investigator in the area of obesity and diabetes gene discovery, using new technology and a genetic system where the role of every gene can be examined systematically. Discovery of obesity and diabetes candidate genes will help both to inform future study of metabolic diseases and to design intelligent therapies to combat these devastating diseases.

描述（由申请人提供）：该提案描述了Alexander Soukas的五年计划，以过渡到具有肥胖和糖尿病功能基因组学专业知识的独立资助研究者。苏卡斯博士是麻省总医院的医学讲师和分子生物学助理，他将接受哈佛医学院遗传学教授Gary Ruvkun博士的指导。Ruvkun博士是秀丽隐杆线虫生物学、代谢、遗传学和基因组学方面的全球专家，拉斯克奖得主，并拥有非常出色的指导记录，指导了38名学员，其中24名具有学术和终身教职。由医学博士David Altshuler、医学博士Joseph Avruch、医学博士Mason Freeman和医学博士Vamsi Mootha组成的具有人类遗传学、脂质代谢、细胞信号和线粒体生物学专业知识的医师科学家咨询委员会将提供科学指导，使研究者在医学相关研究领域获得基础，并在向独立研究者过渡期间提供职业指导。Soukas博士将在麻省总医院和哈佛医学院的研究和培训环境中开展计划的职业发展活动。