My goal as a physician-scientist is to improve the lives of children through research on the pathophysiology of diabetes mellitus. To this end I have spent the past several years training in the laboratory of Dr Morris White investigating the etiology of beta-cell dysfunction in diabetes. This proposal will allow me to further train in cell biology and physiology as I transition to a career as an independently funded investigator in the Joslin Diabetes Center. Little is known about the regulation of beta-cell proliferation, although the insulin-like growth factors (IGFs), other growth factors, and the pancreatic transcription factor Pdx1 may play a role. Insulin Receptor Substrate (IRS)-2 related pathways are essential for beta-cell survival: Irs2 knockout (-/-) mice develop beta-cell failure and insulin resistance resulting in death from diabetes. I have previously shown that Irs2 signaling alters levels of Pdx1, a pancreatic transcription factor that promotes beta-cell mass and function. I also found that Pdx1 overexpression can stimulate beta-cell proliferation in mice, as measured by BrdU incorporation into beta-cells. In most tissues mitogenic stimuli increase gene expression of G1 cyclin D-type cyclins, which partner with cyclin dependent kinase (cdk)-4 or -6 to promote cell growth. Remarkably, cdk4-/- mice develop diabetes from inadequate beta-cell growth. From these findings I suspected that one of the D-type cyclins might be an important partner of cdk4 in islet expansion. Supporting this notion I have recently found that cyclin D2-/- mice develop diabetes with impaired beta-cell growth. Further experiments suggest that Pdx1 could regulate beta-cell proliferation by directly binding to the cyclin D2 promoter. This proposal will test the hypothesis that cyclin D2 is essential for normal islet growth and that Pdx1 regulates beta-cell proliferation by regulating cyclin D2 activity by examining the following specific aims: 1. To test if cyclin D2 is an essential regulator of islet growth. 2. To test if Pdx1 influences beta-cell proliferation by regulating cyclin D2.
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