IGF binding protein-3 in beta cell apoptosis

IGF 结合蛋白 3 在 β 细胞凋亡中的作用

• 批准号: 6605903
• 负责人: ROBERT FERRY
• 金额: $ 13.15万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6605903
• 关键词: NOD mouse; apoptosis; binding proteins; carbohydrate metabolism; cellular pathology; genetically modified animals; growth factor receptors; insulin dependent diabetes mellitus; insulinlike growth factor; laboratory mouse; pancreatic islets; tissue /cell culture

DESCRIPTION (provided by applicant): Autoimmune and non-immune apoptosis, or programmed death, of pancreatic beta cells results in type 1 diabetes mellitus. Normal beta-cell survival entails complex regulation of multiple hormones and fundamental growth factors, including the insulin-like growth factors (IGFs). IGF binding proteins (IGFBPs) sequester IGFs in body tissues and blood, thereby controlling bioavailability of lGFs for their receptors. IGFBPs dramatically impact cell proliferation, apoptosis, and physiology via both IGF-dependent and IGF-independent mechanisms. Work in several cell culture and animal models has confirmed that the pancreatic islets provide a fertile environment for actions of multiple IGF axis components. Manipulating this axis to understand and ultimately control the pathways regulating beta cell survival is key to multiple strategies for restoring insulin secretion. Recently, it has been discovered that IGFBP-3, the major IGFBP in serum, induces apoptosis in diverse cancer cell types via direct, functional interactions with the nuclear retinoic X receptor-alpha (RXR-alpha), the first nuclear receptor identified for any IGFBP. Several cytokines have been implicated in beta cell apoptosis, including tumor necrosis factor-alpha (TNF-alpha). We have recently discovered that TNF-alpha-induced beta cell apoptosis requires de novo transcription of IGFBP-3. Moreover, we have discovered that TNF-alpha induces IGFBP-3 production and increases the nuclear content of IGFBP-3 in beta cells. We have developed two new mouse models; a transgenic designed to specifically over-express IGFBP-3 in the islets, and mice which lack IGFBP-3, but possesses alleles associated with type 1 diabetes (namely the iddm alleles of the non-obese diabetic mouse. These latter NOD/BP3-/-mice appear to manifest improved glucose tolerance in vivo, suggesting that loss of IGFBP-3 may protect from beta-cell apoptosis. These data are compelling to pursue because they present novel targets for controlling beta cell survival and for improving beta cell function. Our central hypothesis is that IGF axis components, IGFBP-3 and IGF-I in particular are critical regulators of beta-cell survival and insulin secretion and therefore play central roles in the pathogenesis of type 1 and type 2 diabetes. We propose to: 1) determine the relationship between IGFBP-3 and RXR-alpha in beta-cell apoptosis and dysfunction; 2) develop novel transgenic rodent models overexpressing select native and mutant IGF axis components in an islet-specific manner; 3) determine the requirement of IGFBP-3 for beta-cell apoptosis in vivo, and 4) assess whether overexpression of IGFBP-3 antagonists in the islets protects NOD mice from developing diabetes. These studies promise to improve our understanding of the pathogenesis of diabetes and may open novel therapeutic approaches to prevention and treatment of diabetes. The UCLA Department of Pediatrics has dedicated extensive resources to support the research activities and career development of its junior faculty. This Department has established mentoring programs to transition junior faculty from dependence to independence, and, ultimately, interdependence as pediatrician scientists. The resources of the candidate's department will leverage the support from this grant on a "dollar-for-dollar" basis, and thereby propel not only the proposed scientific work but also the emergence of the candidate as an independent pediatrician-scientist during the time period of this award.

描述（由申请人提供）： 胰腺β细胞的自身免疫性和非免疫性凋亡或程序性死亡 1型糖尿病的病因是什么？正常的β细胞存活需要 多种激素和基本生长因子的复杂调节， 包括胰岛素样生长因子（IGFs）。IGF结合蛋白（IGFBPs） 隔离身体组织和血液中的IGF，从而控制生物利用度 对它们的受体来说。IGFBPs显著影响细胞增殖， 细胞凋亡，以及通过IGF依赖性和IGF非依赖性 机制等在几种细胞培养和动物模型中的工作已经证实， 胰岛为多种IGF的作用提供了肥沃的环境 轴组件。操纵这个轴来理解并最终控制 调节β细胞存活的途径是多种策略的关键， 恢复胰岛素分泌。 最近，已经发现血清中主要的IGFBP-3， 通过直接的、功能性的、 与核视黄酸X受体-α（RXR-α）的相互作用， 任何IGFBP的核受体。几种细胞因子已经被 参与β细胞凋亡，包括肿瘤坏死因子-α （TNF-α）。我们最近发现TNF-α诱导的β细胞 凋亡需要IGFBP-3的从头转录。而且我们 发现TNF-α诱导IGFBP-3的产生，并增加细胞核的表达。 β细胞中IGFBP-3的含量。我们开发了两种新的小鼠模型; 设计为在胰岛中特异性过表达IGFBP-3的转基因，和 缺乏IGFBP-3但具有与1型糖尿病相关的等位基因的小鼠 （即非肥胖糖尿病小鼠的IDDM等位基因。这些后者 NOD/BP 3-/-小鼠似乎在体内表现出改善的葡萄糖耐量， 这表明IGFBP-3的缺失可以保护β细胞免于凋亡。这些 数据是令人信服的追求，因为他们提出了新的目标， 控制β细胞存活和改善β细胞功能。 我们的中心假设是，IGF轴的组成部分，IGFBP-3和IGF-I， 特别是β细胞存活和胰岛素分泌的关键调节因子 因此在1型和2型糖尿病的发病机制中起重要作用 糖尿病我们建议：1）确定IGFBP-3与 RXR-α在β细胞凋亡和功能障碍中的作用; 2）开发新型转基因 啮齿动物模型过表达选择的天然和突变的IGF轴成分， 胰岛特异性方式; 3）确定β细胞对IGFBP-3的需求 评估IGFBP-3拮抗剂的过表达是否 保护NOD小鼠不患糖尿病。这些研究表明， 提高我们对糖尿病发病机制的认识，并可能开辟新的 预防和治疗糖尿病的治疗方法。 加州大学洛杉矶分校儿科部门投入了大量资源， 研究活动和青年教师的职业发展。这 部门已经建立了指导计划，以过渡初级教师从 从依赖到独立，最终， 科学家候选人所在部门的资源将利用 在“一美元对一美元”的基础上， 不仅是拟议的科学工作，而且是候选人作为一个 独立儿科医生，科学家在此期间的奖项。