Oxidative Stress and the Mitochondrial Proteome in Diabetic Neuropathy

糖尿病周围神经病变(DPN)是糖尿病患者的一种常见并发症，由 神经元和雪旺细胞(SCs)进行性变性。尽管很多人的注意力都集中在 DPN、SCs的神经元丢失也经历了实质性的变性，并且对于重建轴突是至关重要的。 神经胶质相互作用是再生所必需的。高血糖所致的相互关联的代谢损伤分析 血糖升高可能是导致超氧阴离子生成增加的一个焦点事件 为线粒体干杯！干细胞功能障碍与细胞凋亡。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SCs的凋亡。到目前为止，氧化应激和IGF-1的作用 在调节干细胞的线粒体功能方面，他们只关注了一小部分有助于 细胞凋亡。然而，目前尚不清楚干细胞在DPN中是否发生了广泛的凋亡。我们假设 干细胞中超氧化物的产生和IGF-1信号的相反作用在平衡中可能更关键 影响线粒体蛋白表达和翻译后修饰的变化 细胞器动态平衡是调节干细胞再生的中心环节。由于存在显著的差距， 关于葡萄糖诱导的超氧化物歧化和IGF-1信号在维持心脏功能中的广泛作用 线粒体蛋白质组，我们的特定目标是：1)确定葡萄糖诱导的超氧化物歧化的作用 用药理、分子和定量方法改变干细胞线粒体蛋白质组的产物 蛋白质组学方法。2)确定葡萄糖诱导的超氧化物歧化产物在提高水平中的作用 线粒体蛋白质组中的酪氨酸硝化作用。3)确定磷脂的充分性/必要性- 肌醇3激酶在减轻胰岛素样生长因子-1诱导的葡萄糖诱导的超氧化物产生中的作用。总体而言，我们的研究将 识别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.