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: 8486425
• 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/8486425
• 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)：本提案描述了Alexander Soukas过渡到一名独立资助的研究人员的五年计划，该研究人员具有肥胖和糖尿病功能基因组学方面的专业知识。苏卡斯博士是麻省总医院的医学讲师和分子生物学助理，将由哈佛医学院遗传学教授加里·鲁夫昆博士指导。Ruvkun博士是线虫生物学、新陈代谢、遗传学和基因组学方面的全球专家，也是拉斯克奖获得者，他有着非常出色的导师记录，曾指导过38名学员，其中24人拥有学术、终身教职。由David Altshuler(医学博士)、Joseph Avruch(医学博士)、Mason Freeman(医学博士)和Vamsi Mootha(医学博士)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内科科学家咨询委员会将提供科学指导，使研究人员进入与医学相关的研究领域，并在向独立研究人员过渡的过程中提供职业指导。索卡斯博士将在马萨诸塞州总医院和哈佛医学院的研究和培训环境中开展计划中的职业发展活动。 该研究计划建议使用生物体线虫来识别与肥胖和糖尿病发病机制有关的候选基因。肥胖症和2型糖尿病是极其普遍的、高度相关的疾病，2007年美国花费了超过1740亿美元，并在生命年损失方面给社会造成了更大的成本。鉴于古代调节能量稳态的途径具有极大的保守性，我们假设，识别线虫中调节脂肪的保守基因将阐明人类调节能量稳态的遗传途径，甚至可能是肥胖症和糖尿病的疾病机制。对线虫的初步研究已经分离出50多个脂肪含量发生变化的突变株。到目前为止，最值得注意的是保守基因Rictor，它是雷帕霉素复合体2靶蛋白激酶(TORC2)的重要组成部分，以及血清和糖皮质激素诱导激酶(SGK-1)，它是一种与Akt相关的激酶，作用于TORC2下游。已完成的对线虫Rictor的研究表明，它是新陈代谢的中央调节因子，通过调节AKT和SGK4激酶来控制脂肪质量、生长、繁殖和寿命。研究人员将学习应用基因组学(RNA干扰、全基因组测序、高通量技术)、正向遗传学和生物化学1)识别改变线虫脂肪含量的基因的新突变，2)确定Rictor/TORC2和其他突变株产生改变脂肪团的细胞和分子机制，以及3)建立调节身体脂肪的遗传相互作用网络。这项工作的最终目标是识别和表征在线虫和人类的能量稳态中发挥保守作用的基因，为人类遗传和小鼠肥胖和糖尿病的模型研究提供信息，并过渡到独立研究者的地位。 公共卫生相关性：肥胖和2型糖尿病是公认的相关疾病，是导致过早患病和死亡的主要原因之一。该职业发展奖建议进行培训，使申请者成为肥胖症和糖尿病基因发现领域的独立调查者，使用新技术和遗传系统，可以系统地检查每个基因的作用。肥胖和糖尿病候选基因的发现将有助于为未来对代谢性疾病的研究提供信息，并设计智能疗法来对抗这些毁灭性的疾病。