Identifying New Aging and Longevity Genes in Caenorhabditis elegans

描述（由申请人提供）：候选人是丹娜-法伯癌症研究所的肿瘤学研究员，之前接受过哺乳动物细胞凋亡和免疫学的MD-PhD学生的研究培训。他已经回到实验室后，5年的中断花了追求临床培训，包括实习和住院医师在内科和亚专科临床培训在医学肿瘤。他对衰老和长寿产生了兴趣，并希望从事一项职业发展计划，该计划将提供以下领域的培训：（1）衰老生物学（2）功能基因组学和（3）C。线虫作为模式生物和工具。职业发展计划要求在达纳法伯癌症研究所的马克维达尔博士的双重导师下进行培训，他是C.以及马萨诸塞州总医院的加里鲁夫昆博士，他是一位在C.优雅此外，附近还有许多其他机构，共同形成了一个非常丰富和多样化的培训环境。该研究计划提出在C. elegans通过使用组合的功能基因组方法。已知的与C.包含DAF-2胰岛素样信号传导途径的线虫将被用作全基因组酵母双杂交筛选（称为蛋白质相互作用作图的方法）中的诱饵。通过这些筛选鉴定的新相互作用物将进行功能分析，该分析最初将包括RNA介导的干扰（RNAi），以观察功能丧失的表型。最初要检查的表型是dauer形成，因为历史上daf-2途径中改变dauer形成的基因突变也会产生长寿表型。幼虫形式是一种休眠、活动减退和长寿的幼虫形式，可以在恶劣条件下发育，但当条件变得更有利时可以恢复正常发育。初步的数据，提出了确定7个新的相互作用蛋白，其中2个给dauer表型的RNAi。还提出了利用双杂交鉴定候选基因的寿命测定方法。预计蛋白质相互作用图谱和基于RNAi的分析相结合的方法将鉴定出许多参与dauer形成、衰老和长寿的新基因。

DESCRIPTION (provided by applicant): The candidate is an oncology fellow at the Dana-Farber Cancer Institute with prior research training as an MD-PhD student in mammalian apoptosis and immunology. He has returned to the laboratory after a 5 year hiatus spent pursuing clinical training, including internship and residency in Internal Medicine and subspecialty clinical training in Medical Oncology. He has developed an interest in aging and longevity and wishes to pursue a program of career development that will provide training in the areas of (1) biology of aging (2) functional genomics and (3) C. elegans as a model organism and tool. The career development plan calls for training under dual mentors Dr. Marc Vidal at Dana-Farber Cancer Institute, who is a pioneer in functional genomic approaches in C. elegans, as well as Dr. Gary Ruvkun at Massachusetts General Hospital, who is an established investigator in aging and longevity in C. elegans. In addition, there are many other institutions in the immediate vicinity that form a collectively very rich and diverse training environment. The research plan proposes to identify new aging and longevity genes in C. elegans by using a combined functional genomic approach. The known proteins involved in longevity in C. elegans, which comprise the daf-2 insulin-like signaling pathway, will be used as baits in genome-wide yeast two-hybrid screens (an approach termed protein interaction mapping). New interactors identified by these screens will be subject to a functional analysis that will initially consist of RNA-mediated interference (RNAi) to look at loss-of-function phenotypes. The phenotype to be initially examined is dauer formation, since historically mutations in genes in the daf-2 pathway that alter dauer formation also give longevity phenotypes. The dauer form is a dormant, hypoactive and long-lived larval form that can develop under harsh conditions, but that can resume normal development when conditions become more favorable. Preliminary data is presented identifying 7 novel interacting proteins, 2 of which give dauer phenotypes by RNAi. Longevity assays of candidate genes identified by two-hybrid are also proposed. It is anticipated that the combined approach of protein interaction mapping and RNAi-based analysis will identify many new genes involved in dauer formation, aging and longevity.