IGF binding protein-3 in beta cell apoptosis

描述(由申请人提供)： 胰岛β细胞的自身免疫性和非免疫性细胞凋亡或程序性死亡 细胞导致1型糖尿病。正常的β细胞生存需要 对多种激素和基本生长因子的复杂调控， 包括胰岛素样生长因子(IGFS)。胰岛素样生长因子结合蛋白(IGFBPs) 隔离体内组织和血液中的IGF，从而控制生物利用度 LGFS的受体。IGFBPs极大地影响细胞增殖， IGF依赖和非IGF依赖的细胞凋亡和生理学 机械装置。在几种细胞培养和动物模型中的研究证实 胰岛为多种IGF的活动提供了肥沃的环境 轴组件。操纵这个轴来理解并最终控制 调控β细胞存活的途径是多种策略的关键 恢复胰岛素分泌。 最近发现，血清中主要的IGFBP-3， 通过直接的、功能性的诱导多种类型的癌细胞的凋亡 与核维甲酸X受体-α(RXR-α)的相互作用 识别出任何IGFBP的核受体。几种细胞因子已经被 与β细胞凋亡有关，包括肿瘤坏死因子-α (肿瘤坏死因子-α)。我们最近发现，肿瘤坏死因子-α诱导的β细胞 细胞凋亡需要IGFBP-3的从头转录。此外，我们有 发现肿瘤坏死因子-α诱导IGFBP-3的产生并增加核 β细胞中IGFBP-3的含量。我们开发了两种新的老鼠模型；一种 转基因设计，在胰岛中特异性地过表达IGFBP-3，以及 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。这些是后者 NOD/BP3-/-小鼠体内的糖耐量似乎有所改善， 提示IGFBP-3的缺失可能对胰岛β细胞的凋亡有保护作用。这些 数据之所以令人信服，是因为它们提出了新的目标 控制胰岛细胞存活和改善胰岛细胞功能。 我们的中心假设是IGF轴成分、IGFBP-3和IGF-I在 尤其是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型的发病机制中起着核心作用 糖尿病。我们建议：1)确定IGFBP-3和IGFBP-3的关系 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 啮齿动物模型过度表达选择的原生和突变的IGF轴组件 胰岛特异性方式；3)确定IGFBP-3对β细胞的要求 体内细胞凋亡，以及4)评估IGFBP-3拮抗剂是否过表达 保护NOD小鼠免受糖尿病的侵袭。这些研究表明 提高我们对糖尿病发病机制的认识，可能会开启新的 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已投入大量资源支持 其初级教员的研究活动和职业发展。这 系已建立辅导计划，将初级教员从 对独立的依赖，以及最终作为儿科医生的相互依赖 科学家。候选人所在部门的资源将利用 从这笔赠款中获得“美元对美元”的支持，从而推动不 不仅是拟议的科学工作，也是候选人作为 本奖项期间的独立儿科医生-科学家。

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.