Oxidative Stress and the Mitochondrial Proteome in Diabetic Neuropathy

描述（由申请人提供）： 糖尿病周围神经病变（DPN）是糖尿病患者的常见并发症，其起因于神经元和雪旺细胞（SC）的进行性变性。虽然很多注意力集中在DPN中的神经元损失上，但是SC也经历实质性变性，并且对于重建再生所必需的轴突相互作用至关重要。对由高血糖引起的相互关联的代谢损伤的分析已经确定，超氧阴离子的产生增加可能是导致线粒体损伤的焦点事件。功能障碍和细胞凋亡。另一方面，胰岛素样生长因子-1（IGF-1）可降低SC的线粒体功能障碍和凋亡。迄今为止，氧化应激和IGF-1在调节干细胞线粒体功能中的作用仅集中在一小部分促进细胞凋亡的蛋白质上。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的相反的影响可能是更关键的平衡变化，在表达和翻译后修饰的线粒体蛋白质，影响方面的细胞器的稳态中央调节SC再生。由于葡萄糖诱导的超氧化物产生和IGF-1信号在维持线粒体蛋白质组方面的广泛作用存在显著差距，因此我们的具体目标是：1）使用药理学，分子和定量蛋白质组学方法确定葡萄糖诱导的超氧化物产生在改变SC的线粒体蛋白质组中的作用。2)线粒体蛋白质组中酪氨酸硝化的鉴定。3)鉴定磷脂酰肌醇3激酶在IGF-1减弱葡萄糖诱导的超氧化物产生中的充分性和必要性。总的来说，我们的研究将确定对葡萄糖诱导的氧化应激敏感的线粒体蛋白，并提高我们对生长因子信号传导如何改善糖尿病神经中线粒体功能的理解。

DESCRIPTION (provided by applicant): 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 axonglial interaction necessary for regeneration. Analysis of the inter-related metabolic insults induced by hyperglycemia 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 has 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 of tyrosine nitration in the mitochondrial proteome. 3) Identify the sufficiency and necessity of phosphatidylinositol 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.