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: 8281499
• 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/8281499
• 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，旨在转型为一名独立资助的研究人员，拥有肥胖和糖尿病功能基因组学方面的专业知识。苏卡斯博士是马萨诸塞州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加里·鲁夫昆博士的指导。 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，拉斯克奖获得者，并拥有非常出色的指导记录，指导过 38 名学员，其中 24 名拥有学术、终身教授职位。由具有人类遗传学、脂质代谢、细胞信号传导和线粒体生物学专业知识的医师科学家组成的咨询委员会由 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，该委员会将提供科学方向，为研究者奠定医学相关研究领域的基础，并提供职业指导 在向独立调查员过渡期间。苏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秀丽隐杆线虫来识别与肥胖和糖尿病发病机制有关的候选基因。肥胖和 2 型糖尿病是极其普遍、高度相关的疾病，2007 年给美国造成的损失超过 1740 亿美元，并且在生命年损失方面给社会带来了更大的损失。鉴于调节能量稳态的古代途径具有巨大的保守性，我们假设鉴定秀丽隐杆线虫中调节脂肪的保守基因将阐明调节能量稳态的人类遗传途径，甚至可能阐明肥胖和糖尿病的疾病机制。对秀丽隐杆线虫的初步研究已分离出 50 多个脂肪含量发生改变的突变体。迄今为止发现的最值得注意的是保守基因 rictor，它是雷帕霉素复合物 2 (TORC2) 蛋白激酶靶标的重要组成部分，以及血清和糖皮质激素诱导激酶 (sgk-1)，它是一种作用于 TORC2 下游的 Akt 相关激酶。对秀丽隐杆线虫 rictor 的完整研究表明，它是代谢的中心调节因子，通过调节激酶 AKT 和 SGK4 来控制脂肪量、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新突变，2）确定 rictor/TORC2 和其他突变体中产生改变脂肪量的细胞和分子机制，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秀丽隐杆线虫和人类能量稳态中发挥保守作用的基因，为肥胖和糖尿病的人类遗传和小鼠模型研究提供信息，并过渡到独立研究者身份。 公共卫生相关性：肥胖和 2 型糖尿病是公认的相关疾病，是过早患病和死亡的主要原因之一。该职业发展奖提议进行培训，使申请人成为肥胖和糖尿病基因发现领域的独立研究者，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代谢疾病的研究提供信息，并设计智能疗法来对抗这些毁灭性疾病。