Oxidative Stress Induces Apoptosis in Diabetic Neurons

描述（由申请人提供）：糖尿病最常见的并发症 是神经病变，发生在超过50%的糖尿病患者中。先前 研究表明，糖尿病高血糖与细胞凋亡有关， 神经元这项提案旨在了解葡萄糖如何杀死和IGF-I拯救 在细胞培养物和糖尿病神经病变的动物模型中的神经元。我们的工作 产生了一个新的理论在糖尿病神经元中， 活性氧物质（ROS），包括一氧化氮（NO）和过氧亚硝酸盐。 这导致线粒体内膜（Mt）的去极化， 细胞色素c释放到胞质溶胶中，并诱导半胱天冬酶介导 程序性细胞死亡（PCD）。相反，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（UCP 2和 UCP 3）通过磷脂酰肌醇3激酶（PI 3 K）介导的途径。 UCP 2或UCP 3的调节导致Mt膜的稳定 潜在的，并抑制起始半胱天冬酶，包括半胱天冬酶-9， 和效应半胱天冬酶，如半胱天冬酶-3。阻断高甘油ROS 诱导PCD可能为糖尿病神经病变提供新的治疗方法。这一模式将 使用初级感觉神经元，PC 12细胞， 和II型糖尿病的大鼠模型。我们有3个目标：1）表征葡萄糖 和IGFI控制ROS诱导的PCD，2）表征IGF-I上调UCPs 预防ROS诱导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.