Cyclin D2 Regulation Of Islet Growth

描述（由申请人提供）： 作为一名医生和科学家，我的目标是通过研究糖尿病的病理生理学来改善儿童的生活。为此，我在过去几年里一直在Morris白色博士的实验室接受培训，研究糖尿病中β细胞功能障碍的病因。这项建议将使我能够进一步培训细胞生物学和生理学，因为我过渡到乔斯林糖尿病中心独立资助的研究人员的职业生涯。 尽管胰岛素样生长因子（IGFs）、其他生长因子和胰腺转录因子Pdx 1可能发挥作用，但对β细胞增殖的调控知之甚少。胰岛素受体底物（IRS）-2相关通路对β细胞存活至关重要：Irs 2敲除（-/-）小鼠发生β细胞衰竭和胰岛素抵抗，导致糖尿病死亡。我以前已经表明，Irs 2信号改变了Pdx 1的水平，Pdx 1是一种促进β细胞质量和功能的胰腺转录因子。我还发现，Pdx 1过表达可以刺激小鼠的β细胞增殖，这是通过BrdU掺入β细胞来测量的。在大多数组织中，促有丝分裂刺激增加G1期细胞周期蛋白D型细胞周期蛋白的基因表达，其与细胞周期蛋白依赖性激酶（cdk）-4或-6合作促进细胞生长。值得注意的是，cdk 4-/-小鼠由于β细胞生长不足而患上糖尿病。根据这些发现，我怀疑其中一种D型细胞周期蛋白可能是cdk 4在胰岛扩张中的重要伙伴。支持这一观点，我最近发现，细胞周期蛋白D2-/-小鼠患糖尿病的β细胞生长受损。进一步的实验表明，Pdx 1可以通过直接结合细胞周期蛋白D2启动子来调节β细胞增殖。该提案将通过检查以下具体目标来检验细胞周期蛋白D2对正常胰岛生长至关重要以及Pdx 1通过调节细胞周期蛋白D2活性来调节β细胞增殖的假设： 1.检测细胞周期蛋白D2是否是胰岛生长的重要调节因子。 2.检测Pdx 1是否通过调节细胞周期蛋白D2影响β细胞增殖。

DESCRIPTION (provided by applicant): 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.