The long-term goal of our research is to elucidate the molecular and biochemical mechanisms of insulin receptor signal transduction and its potential role in aging. Studies from nematodes and flies have suggested that decreasing insulin signaling may lead to an extended life-span in these animals. However, whether insulin signaling plays a role in regulating the life-span of mammals remains to be tested. Our preliminary studies have shown that expression of Grb10, an Src- homology-homology-2 (SH2) and pleckstrin-homology (PH) domain- containing adaptor protein which binds specifically to the kinase domain of autophosphorylated insulin receptor, is greatly decreased in the brain of aged mice compared to brain to young mice. Since Grb10 negatively regulates insulin signaling in mammalian cells, we hypothesize that the decrease of Grb10 expression in the brain may correlates with an enhanced insulin signal transduction and aging process. To test this hypothesis, we propose to generate a transgenic mice model that over- express Grb10 in the neurons.
The specific aims of this research are: 1) to generate a neuron-specific Grb10 transgenic vector; 2) to produce and select Grb10 transgenic mice and 3) to Characterize the in vivo roles of Grb10 in insulin signaling. This study will provide us with a novel animal model to study the potential involvement of insulin signaling in animal aging.
