Identifying New Aging and Longevity Genes in Caenorhabditis elegans

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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.