Department Department of Medicine, Division of Endocrinology, Diabetes & Hypertension Research Group Hillblom Islet Research Center Office Phone (310) 206-5368 E-mail: abhushan@mednet.ucla.edu Office Location 900A Weyburn Place North Los Angeles, CA 90095-7345

Anil Bhushan, PhD The long-term goal of my research is to understand the molecular mechanisms that govern beta cell formation during embryogenesis and the expansion/regeneration of beta cell mass in adult and diabetes animal models. Strategies for tackling these complex problems include the generation and analysis of null mouse mutants, development of cell-type-specific inducible transgenic mice, as well as in vitro islet cultures to study metabolic characteristics. To understand how beta cells develop from undifferentiated cells we have focused on deciphering how complex patterning information controlling fundamental cellular processes such as differentiation and proliferation of pancreatic progenitor is integrated during the process of organogenesis. The progenitor cells during the early development of the pancreas simultaneously receive multiple signals, some mitogenic and some inducing differentiation. These extrinsic signals are interpreted through an intrinsic mechanism that either commits the progenitor cell to the mitotic cell cycle or lead to exit from the cell cycle in order to differentiate. Work from our laboratory has identified genes involved in this binary decision process of progenitor cells during the development of the pancreas. Several of these genes are cell cycle regulators acting in the G1 phase, including cyclins and cyclin-dependent kinase inhibitors. Such an approach will allow identification of steps needed to drive cells from an immature embryonic state to a fully formed beta cells and will be essential for devising therapeutic approaches to diabetes. Another interest of the laboratory is to understand how beta cell mass expands to compensate for the changing insulin demand. Manipulation of beta cell mass can be an effective strategy to treat diabetes as increasing evidence suggests that variations in insulin demand can lead to marked changes in the beta cell mass and the inability of the endocrine pancreas to compensate for the changing insulin demand can contribute to the pathogenesis of diabetes can contribute to the pathogenesis of diabetes. We wish to understand how the metabolic and hormonal status of the cell affects can affect beta cell growth and proliferation. We have focused on cell cycle regulators that can translate the metabolic demands on beta cells into regulation of beta cell proliferation. Studies from our laboratory have established that cyclin D2-mediated proliferation was essential in the regulation of postnatal beta cell mass. More recently, we have show that the transition of beta cells from quiescence to proliferation is controlled by p27, a negative regulator of cyclin D2-mediated proliferation. We showed that quiescent beta cells accumulate p27 and disabling p27 in these cells allows them to divide. Thus the cellular abundance of p27 is a critical determinant of whether a beta cell divides or remains quiescent. In mouse models of type 2 diabetes, beta cells accumulated p27 and hyperglycemia was prevented with the deletion of p27. We now are studying how the mechanisms that control the cellular abundance of p27 could play a key role in translating the metabolic demands on beta cells into regulation of beta cell mass.