Obesity and diabetes genetics in Caenorhabditis elegans.

描述（由申请人提供）：该提案描述了亚历山大索卡过渡到一个独立资助的研究者在肥胖和糖尿病的功能基因组学的专业知识的五年计划。Soukas博士是马萨诸塞州总医院的医学讲师和分子生物学助理，他将接受加里·鲁夫昆博士的指导，哈佛医学院的遗传学教授。Ruvkun博士是C.他是一名优秀的生物学、代谢、遗传学和基因组学教授，曾获得拉斯克奖，并有很好的指导记录，曾指导过38名学员，其中24人拥有学术、终身教职。由医学博士大卫阿尔特什韦尔组成的一个咨询委员会，由在人类遗传学、脂质代谢、细胞信号传导和线粒体生物学方面具有专长的医生科学家组成，博士，Joseph Avruch，医学博士，梅森·弗里曼医学博士和Vamsi Motha，医学博士将提供科学指导，在医学相关的研究领域为研究者提供基础，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有机体C。elegans来鉴定参与肥胖和糖尿病发病机制的候选基因。肥胖和2型糖尿病是非常普遍的，高度相关的疾病，在2007年花费了美国超过1740亿美元，并且在生命年损失方面对社会产生更大的成本。考虑到在古老的能量平衡调节途径中的巨大保守性，我们假设在C。秀丽隐杆线虫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发病机制。对C.秀丽线虫已经分离出50多种脂肪含量改变的突变体。迄今为止，最值得注意的是保守基因rictor，雷帕霉素复合物2（TORC 2）蛋白激酶靶点的重要组成部分，以及血清和糖皮质激素诱导的激酶（sgk-1），一种作用于TORC 2下游的Akt相关激酶。已完成的C. elegans rictor的研究表明，它是代谢的中心调节剂，通过调节激酶AKT和SGK 4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）来识别改变C基因的新突变。线虫脂肪含量，2）确定在rictor/TORC 2和其他突变体中产生改变的脂肪量的细胞和分子机制，以及3）建立调节体脂的遗传相互作用网络。这项工作的最终目标是确定和表征在C. elegans和人类，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，是过早患病和死亡的主要原因之一。该职业发展奖旨在通过培训，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，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的代谢性疾病研究提供信息，并设计智能疗法来对抗这些毁灭性疾病。

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.