Cell Cycle Control of Beta-Cell Mass

β 细胞团的细胞周期控制

• 批准号: 7261357
• 负责人: Anil Bhushan
• 金额: $ 27.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-05 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261357
• 关键词: Animal Model; Beta Cell; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cell Therapy; Cells; Complex; Data; Degradation Pathway; Development; Diabetes Mellitus; Engraftment; Failure; Fostering; Goals; Grant; Growth; Hyperglycemia; Insulin Resistance; Knock-in Mouse; Knockout Mice; Laboratories; Mediating; Metabolic Diseases; Methods; Molecular; Mus; Mutant Strains Mice; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Phosphorylation; Proliferating; Proteins; Regulation; Research Personnel; Role; SKP Cullin F-Box Protein Ligases; Specificity; Therapeutic; Transgenic Mice; Transplantation; Work; cyclin D2; improved; islet; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; postnatal; prevent; programs; receptor; ubiquitin ligase

DESCRIPTION (provided by applicant): Understanding the molecular mechanisms governing beta cell proliferation has important ramification for fostering beta cell regeneration and the treatment of diabetes. Studies supported by a pilot 2 year collaborative grant established that cyclin D2-mediated proliferation was essential in the regulation of postnatal beta cell mass. We also demonstrated 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. We now present preliminary data to demonstrate that ubiquitin ligase-mediated degradation pathways regulate the cellular abundance of p27 and the progression of beta cell proliferation. We also show that pathways regulating p27 turnover could be involved in accumulating p27 in beta cells of animal models of type 2 diabetes. In the next five years we will endeavor to integrate mechanisms of p27 turnover and their role in metabolic disorders. We propose to study: Aim 1, the ubiquitin ligase-mediated degradation pathways that regulate cell cycle progression of beta cells and their role in beta cell compensatory growth in insulin resistance animal models; in Aim 2, to utilize p27 degradation pathways to promote beta cell expansion/regeneration; Aim 3, how p27 degradation pathways contribute to beta cell failure during the development of type 2 diabetes in animal models; Aim 4, to examine whether targeting p27 could be beneficial for cell-based therapies in which the extent of cell proliferation could have potential benefit. These studies will be carried out using null mouse mutants, beta cell-specific inducible transgenic mice, and cultured islet, using methods that are fully implemented in the laboratory. The goal of this work is to find a therapeutic approach for modifying p27 function and we hope that by identifying mechanisms of p27 turnover, new ways to modulate its function in a controlled fashion can be found.

描述（由申请人提供）：了解控制β细胞增殖的分子机制对于促进β细胞再生和治疗糖尿病具有重要意义。一项为期2年的试点合作基金支持的研究表明，细胞周期蛋白D2介导的增殖在调节出生后β细胞群中至关重要。我们还证明了β细胞从静止到增殖的转变是由p27控制的，p27是细胞周期蛋白D2介导的增殖的负调节因子。我们发现，静止的β细胞积累p27， 这些细胞中的p27允许它们分裂。因此，p27的细胞丰度是β细胞分裂或保持静止的关键决定因素。我们现在提出的初步数据表明，泛素连接酶介导的降解途径调节细胞丰度的p27和β细胞增殖的进展。我们还表明，调节p27周转的途径可能参与2型糖尿病动物模型β细胞中p27的积累。在接下来的五年里，我们将奋进整合p27周转机制及其在代谢紊乱中的作用。我们建议研究：目的1、泛素连接酶介导的β细胞周期降解途径及其在胰岛素抵抗动物模型中β细胞代偿性生长中的作用;目的2、利用p27降解途径促进β细胞扩增/再生; 目的3，p27降解途径如何在2型糖尿病动物模型的发展过程中促进β细胞衰竭;目的4，检查靶向p27是否有利于基于细胞的治疗，其中细胞增殖的程度可能具有潜在的益处。这些研究将使用无效小鼠突变体、β细胞特异性诱导型转基因小鼠和培养的胰岛，使用在实验室中完全实施的方法进行。这项工作的目标是找到一种治疗方法来改变p27的功能，我们希望通过确定p27营业额的机制，可以找到新的方法来调节其功能在一个可控的方式。