AKT/mTOR Signaling and Regulation of Cell Cycle in beta Cells

Washington University, Saint Louis MO

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Pancreatic beta-cell failure is a critical determinant for the development of diabetes. In spite of the importance of beta-cell mass in diabetes, there is a lack in the knowledge base that centers on how beta-cells enter the cell cycle and proliferate. Akt is one of the promising molecules identified as a potential target to induce proliferation and survival of beta-cells. Preliminary studies show that Akt alters beta-cell proliferation by activation of the cyclin D/cdk4 complex. The objective of this proposal is to delineate the molecular genetic mechanisms that link Akt to activation of the cyclin D/cdk4 complex. The hypothesis to be tested is that Akt signaling induces beta-cell proliferation by translational control of cyclin D/cdk4 complex components. This will be accomplished via three distinct strategies: Aim 1 will determine the effects of Akt/TSC/mTOR-mediated translational control in beta-cell proliferation. These experiments will performed in animal models with increased and decreased mTOR signaling in beta-cells. In vitro characterization, cell cycle analysis and assessment of protein of cyclin D/cdk4 complex components using islets from these mice will be complemented by in vitro experiments in insulinoma cell lines. Aim 2 will establish the role of rapamycin sensitive (TORC1) and insensitive pathways (TORC2) in beta-cell proliferation induced by activation of Akt/mTOR signaling. The approach used includes characterization, activity and proliferative role of TORC 1 and 2 complexes components in islets and insulinoma cells with altered TORC1 and 2 signaling. Aim 3 will identify the importance of S6K-dependent pathway in beta-cell proliferation induced by Akt/mTOR/TORC1 -dependent signaling. Experiments include transgenic and in vitro models with increased and decreased S6K signaling in beta-cells. Knowing the oncogenic potential of Akt, the research proposed in this application is significant because it will delineate potential downstream events and components that separate proliferative responses from oncogenic potential. This is expected to have a positive impact for the design of pharmaceutical agents that will induce selectively beta-cell proliferation without altering the risk of oncogenic transformation. These agents could be used in translational experiments to treat diabetes by expanding beta-cell mass in vivo, increase the pool of transplantable islets and enhance the success of islet transplantation. Another major impact of these studies is obtaining a better understanding of the effects of rapamycin in beta-cells mass and function. [unreadable] [unreadable] [unreadable]