p130 Regulation of Islet Growth

p130 胰岛生长的调节

• 批准号: 7291416
• 负责人: JAKE ALDEN KUSHNER
• 金额: $ 8.25万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291416
• 关键词: Acute; Adult; Age; Age-Years; Beta Cell; Biological Preservation; Cell Cycle Progression; Cell Proliferation; Cell division; Cell physiology; Cells; Cyclin-Dependent Kinase 4; Cyclins; Daily; Data; Diabetes Mellitus; Drops; Elderly; G0 Phase; Goals; Growth; Insulin-Dependent Diabetes Mellitus; Knockout Mice; Molecular; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Patients; Proliferating; Proteins; Publishing; RBL2 gene; Regulation; Research; Role; Testing; Tissues; Transcriptional Activation; Transplantation; Up-Regulation; Week; base; cell growth; cyclin D2; human RBL2 protein; improved; insulin secretion; islet; prevent; response; transplantation typing; tumor

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.

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，并且对于成人β细胞生长是必需的。细胞周期蛋白D2必须通过激活细胞周期蛋白依赖性激酶-4以磷酸化下游靶点来促进β细胞中的细胞周期进程。此外，我们的新的初步证据有力地表明，“口袋蛋白”（pRb/p107/p130）是下游调节β-细胞增殖：急性缺失Rb在成人β-细胞刺激增殖~3倍。尽管这一重要结果加强了pRb的重要作用，但尽管急性Rb缺乏，85%的成人β-细胞在两周内未能增殖。因此，其他因素必须限制β-细胞增殖。p130（又名：pRb 2）是一个有吸引力的候选者，因为它使一些细胞维持在静止（G 0）状态。基于初步的数据，我们假设p130关键调节β细胞增殖。在这里，我们提出假设驱动的研究，从遗传上询问β细胞增殖的p130依赖性调节。因此，以下具体目标：1.确定p130在β细胞增殖中的作用; 2.研究p130和pRb具有协同作用以限制β细胞增殖的假设。我们过去的研究表明，细胞周期蛋白D2，特别是，有一个必不可少的作用，以控制细胞周期进程的β细胞。因此，该提案中包含的研究代表了确定β细胞增殖的分子调控的独特机会，以实现β细胞功能再生的目标。提高对β细胞生长的理解是一个重要的目标，可以使1型或2型糖尿病患者受益，从而保护2型糖尿病患者的胰岛素分泌，或扩大胰岛移植到1型糖尿病患者体内。在这里，我们提出的研究，从遗传学上询问的作用p130，在细胞分裂中的关键组成部分，在β细胞生长。