Oxidative Stress and the Mitochondrial Proteome in Diabetic Neuropathy

糖尿病周围神经病变（DPN）是糖尿病个体中的常见并发症，其由以下原因引起： 神经元和雪旺细胞（SC）的进行性变性。虽然很多注意力都集中在 DPN中的神经元损失，SC也经历实质性变性，并且对于重建轴突至关重要。 再生所必需的神经胶质相互作用。高脂血症相关代谢损伤的分析 科学家们已经确定，超氧阴离子产生的增加可能是一个焦点事件， 线粒体！功能障碍和细胞凋亡。另一方面，胰岛素样生长因子-1（IGF-1） 减少线粒体功能障碍和SC的凋亡。到目前为止，氧化应激和IGF-1的作用 在调节干细胞线粒体功能方面，只关注了一小部分有助于 凋亡然而，目前尚不清楚DPN中SC是否发生广泛的凋亡。我们假设 超氧化物产生和IGF-1信号在SC中的相反作用可能在平衡中更关键 线粒体蛋白的表达和翻译后修饰的变化， 细胞器稳态方面的中央调节SC再生。由于存在重大差距， 关于葡萄糖诱导的超氧化物产生和IGF-1信号在维持胰岛素抵抗中的广泛作用， 线粒体蛋白质组，我们的具体目标是：1）确定葡萄糖诱导的超氧化物的作用 使用药理学、分子和定量方法， 蛋白质组学方法2)确定葡萄糖诱导的超氧化物产生在提高 线粒体蛋白质组中的酪氨酸硝化。3)确定磷脂酰的充分性/必要性 胰岛素样生长因子-1抑制葡萄糖诱导的超氧化物生成的肌醇3激酶。我们的研究将 鉴定对葡萄糖诱导的氧化应激敏感的线粒体蛋白，并改善我们的 了解生长因子信号传导如何改善糖尿病神经中的线粒体功能。

Diabetic peripheral neuropathy (DPN) is a common complication in diabetic individuals that results from a progressive degeneration of neurons and Schwann cells (SCs). Although much attention has focused on neuronal loss in DPN, SCs also undergo substantial degeneration and are critical for re-establishing axon- glial interaction necessary for regeneration. Analysis of the inter-related metabolic insults induced by hyper- glycemia have identified that increased production of superoxide anion may be a focal event that contributes to mitochondria! dysfunction and apoptosis of SCs. On the other hand, insulin-like growth factor-1 (IGF-1) decreases mitochondrial dysfunction and apoptosis of SCs. To date, the role of oxidative stress and IGF-1 in regulating mitochondrial function in SCs have focused only on a small subset of proteins that contribute to apoptosis. However, it is unclear that SCs undergo extensive apoptosis in DPN. We hypothesize that the opposing effects of superoxide production and IGF-1 signaling in SCs may be more critical in balancing changes in both the expression and post-translational modification of mitochondrial proteins that affect aspects of organellar homeostasis central to regulating SC regeneration. Since a significant gap exists with regard to the broad effect of glucose-induced superoxide production and IGF-1 signaling in maintaining the mitochondrial proteome, our specific aims are to: 1) Identify the role of glucose-induced superoxide production in altering the mitochondrial proteome of SCs using pharmacological, molecular and quantitative proteomic approaches. 2) Identify the role of glucose-induced superoxide production in enhancing the level of tyrosine nitration in the mitochondrial proteome. 3) Identify the sufficiency/necessity of phosphatidyl- inositol 3 kinase in attenuating glucose-induced superoxide production by IGF-1. Collectively, our studies will identify mitochondrial proteins that are susceptible to glucose-induced oxidative stress and improve our understanding of how growth factor signaling may improve mitochondrial function in diabetic nerve.