Oxidative Stress Induces Apoptosis in Diabetic Neurons

描述(申请人提供)：糖尿病最常见的并发症 是神经病变，超过50%的糖尿病患者会发生这种情况。上一首 研究表明，糖尿病高血糖与细胞凋亡有关 神经元。这项建议旨在了解葡萄糖如何杀死和IGF-I拯救 细胞培养和糖尿病神经病变动物模型中的神经元。我们的工作 产生了一种新的理论。在糖尿病神经元中，高糖上调 活性氧(ROS)，包括一氧化氮(NO)和过氧亚硝酸盐。 这导致内线粒体(MT)膜的去极化， 细胞色素c释放到胞浆中，并诱导caspase的介导 程序性细胞死亡(PCD)。相比之下，胰岛素样生长因子I(IGF-I)， 激活IGF-I受体并调节解偶联蛋白2和3(UCP2和 UCP3)通过磷脂酰肌醇3K(PI3K)介导的途径。 调节UCP2或UCP3导致mt膜稳定 并抑制包括caspase-9在内的启动子caspase的激活， 以及效应型caspase，如caspase-3。中断性高甘油ROS 诱导性PCD可能为糖尿病神经病变提供新的治疗方法。这款车型将是 在体外和体内测试，使用初级感觉神经元，PC12细胞， 以及II型糖尿病的大鼠模型。我们有三个目标：1)表征葡萄糖 和IGFI对ROS诱导的PCD的调控；2)IGF-I上调UCPs的特征 预防ROS引起的线粒体功能障碍和PCD，以及3) 描述ROS、NO和UCPs在糖尿病神经病变中的作用。

DESCRIPTION (provided by applicant): The most common complication of diabetes is neuropathy, which occurs in more than 50% of diabetic patients. Previous research shows that diabetic hyperglycemia is associated with apoptosis in neurons. This proposal aims to understand how glucose kills and IGF-I rescues neurons in both cell culture and animal models of diabetic neuropathy. Our work has resulted in a novel theory. In diabetic neurons, high glucose up-regulates reactive oxygen species (ROS) including nitric oxide (NO) and peroxinitrites. This results in depolarization of the inner mitochondrial (Mt) membrane, release of cytochrome c into the cytosol, and induction of caspase mediated programmed cell death (PCD). In contrast, insulinlike growth factor I (IGF-I), activates the IGF-I receptor and regulates uncoupling proteins 2 and 3 (UCP2 and UCP3) through a phosphatidylinositol 3kinase (PI3K)-mediated pathway. Regulation of UCP2 or UCP3 results in stabilization of the Mt membrane potential, and inhibits activation of initiator caspases, including caspase-9, and effector caspases, such as caspase-3. Interrupting hyperglycernic ROS induced PCD may offer new therapy for diabetic neuropathy. This model will be tested both in vitro and in vivo, using primary sensory neurons, PC12 cells, and a rat model of type II diabetes. We have 3 Aims: 1) Characterize glucose and IGFI control of ROS induced PCD, 2) characterize IGF-I up-regulation of UCPs in preventing ROS induced mitochondrial dysfunction and PCD, and 3) characterize the role of ROS, NO, and UCPs in diabetic neuropathy.