If awarded, this R03 grant would provide supplemental funding during the final two years of the applicant's K08 award. The additional funding would provide crucial resources, such as technical assistance, that would enhance the applicant's ability to compete for further grant support and would facilitate establishment as an independent researcher. Type 2 diabetes mellitus affects 18 million Americans, seriously impacting on their quality of life and longevity. Type 2 diabetes mellitus is caused primarily by impaired signaling by insulin. The signaling pathways that are activated within the first ten to fifteen minutes of hormone treatment by insulin or the highly related growth factor IGF-1 have been studied extensively. Surprisingly little is known about membrane-proximal signaling events over longer, more physiologically relevant, time-courses or in response to falling insulin levels. This grant application proposes to study the behavior of the crucial PI-3-kinase pathway over long time-courses in response to rising or falling insulin or IGF-1 levels using powerful imaging techniques that we developed during our research funded by the associated K08 award to track the PI-3-kinase pathway. We also propose a screen to identify novel targets of Ptdlns(3,4,5)P3 as potentially novel elements in the insulin/IGF-1 signaling pathway. We expect that improved understanding of the insulin signaling pathway will eventually lead to improved treatment strategies for insulin resistance and type II diabetes mellitus.
