In humans, an insulin pathway couples nutritional status to metabolism in most tissues. Similarly, an insulin-like pathway in the nematode C. elegans responds to nutritional conditions and other environmental cues to regulate metabolism, entry into a diapaused developmental stage, and longevity. Extended life span caused by down-regulation of the insulin-receptor-like activity in C. elegans is reminiscent of and possibly mechanistically homologous to increased life span caused by caloric restriction in mammals. Signals emanating from the C. elegans insulin-like receptor (daf-2) target a key forkhead transcription factor (daf-16) for inactivation. Several conserved components of this signaling cascade have been previously identified. The goal of this project is to genetically identify more components that affect diapause and aging process by interacting with or functioning downstream of the insulin-like pathway in C.elegans. I proposed to perform three novel genetic screens to isolate such new components. From my preliminary studies, I have obtained multiple interesting mutants. I will further characterize them, along with more mutants I may isolate in the future. Further more I will employ a combination of genetic, molecular and biochemical approaches to find out how these components function and how they interact with the known components in the insulin-like pathway. These studies may shed light on how human insulin pathway exert its function and how it may impact human aging process. In addition, based on preliminary genetic studies, I have discovered in C. elegans a new output of the daf-2/IR-mediated signal that exerts its function in a daf-16/FH-independent manner, which suggests that daf-16/FH may not be the only target of the daf-2/IR signal. I also propose to identify the target gene(s) of this new output of the daf-2/IR signal.
