p130 Regulation of Islet Growth

描述(由申请人提供)： 我们研究的总体目标是确定成人β细胞增殖的分子调控。我们最近发现，细胞周期蛋白D2是β细胞中主要的D型细胞周期蛋白，对成年β细胞的生长是必不可少的。细胞周期蛋白D2必须通过激活细胞周期蛋白依赖的激酶-4来磷酸化下游靶标，从而促进β细胞的细胞周期进程。此外，我们新的初步证据有力地表明，“口袋蛋白”(pRb/p107/p130)位于下游，调节(-细胞增殖：成人(-细胞)Rb的急性缺失刺激了~3倍的增殖。尽管这一显著的结果加强了pRb的重要作用，但85%的成人(-)细胞在急性Rb缺乏的情况下两周内未能增殖。因此，其他因素肯定会限制(-细胞的增殖。P130(又名PRb2)是一个有吸引力的候选者，因为它将一些细胞保持在静止(G0)状态。根据初步数据，我们假设p130对β细胞的增殖起关键调控作用。在这里，我们建议进行假设驱动的研究，以从基因上询问p130对β细胞增殖的依赖调节。因此，本研究的具体目的如下：1.确定p130在胰岛β细胞增殖中的作用；2.探讨p130和pRb协同作用抑制胰岛细胞增殖的假说。我们过去的研究表明，细胞周期蛋白D2对控制β细胞的细胞周期进程具有重要作用。因此，这项提案中包含的研究代表了一个独特的机会来确定β细胞增殖的分子调控，以实现β细胞功能再生的目标。改善对β细胞生长的了解是一个重要的目标，可以使1型或2型糖尿病患者受益，使2型糖尿病患者的胰岛素分泌得以保存，或扩大胰岛移植到1型糖尿病患者的体内。在这里，我们建议进行研究，从基因上询问p130在细胞分裂中的关键成分在β细胞生长中的作用。

DESCRIPTION (provided by applicant): The overall goal of our research is to determine the molecular regulation of adult beta-cell proliferation. We recently discovered that cyclin D2 is the major D-type cyclin in beta-cells, and is essential for adult beta-cell growth. Cyclin D2 must promote cell cycle progression in beta-cells by activating cyclin dependent kinase-4 to phosphorylate downstream targets. Moreover, our new preliminary evidence strongly suggests that the "pocket proteins" (pRb/p107/p130) are downstream to regulate (-cell proliferation: Acute deletion of Rb in adult (-cells stimulates proliferation ~3 fold. Although this significant result reinforces the important role of pRb, 85% of adult (-cells failed to proliferate by two weeks despite acute Rb deficiency. Thus, other factors must limit (-cell proliferation. p130 (a.k.a. pRb2) is an attractive candidate, as it maintains some cells in a quiescent (G0) state. Based on preliminary data, we hypothesize that p130 critically regulates beta cell proliferation. Here, we propose hypothesis-driven studies to genetically interrogate p130 dependent regulation of beta-cell proliferation. Thus, the following specific aims: 1. Determine the role of p130 in beta-cell proliferation; 2. Investigate the hypothesis that p130 and pRb have synergistic effects to restrict beta-cell proliferation. Our past studies reveal that cyclin D2, in particular, has an essential role to control cell cycle progression of beta-cells. Thus, the studies contained within this proposal represent a unique opportunity to determine the molecular regulation of beta-cell proliferation, towards the goal of regeneration of beta-cell function. Improved understanding of beta-cell growth is an important goal that could benefit patients with type 1 or type 2 diabetes, allowing preservation of insulin secretion in patients with type 2 diabetes, or expansion of islets for transplant into patients with type 1 diabetes. Here, we propose studies to genetically interrogate the role of p130, a key component in cell division, in beta-cell growth.