Metabolic Regulation of the Schwann Cell Injury Response

糖尿病周围神经病变是一种越来越常见的疾病，高达25%的糖尿病患者受到影响。糖尿病神经病变的病理基础是轴突完整性和功能的丧失。除了轴突丢失外，损伤后神经纤维再生受损在糖尿病患者中很常见，在啮齿动物糖尿病模型中也是如此。轴突损伤引发围绕受损轴突周围的雪旺细胞(SCs)的戏剧性重新编程，最终导致采用‘修复SC’表型。修复SC促进轴突/髓鞘的分解和处置，吸引巨噬细胞，产生神经营养因子，并阐述黏附分子。一旦与再生的轴突接触，它就会转化回分化的SC，以确保重新髓鞘形成或Remak束的形成。这种修复SC转换的主要调节因子是转录因子c-jun，它在损伤后迅速激活 损伤轴突周围的SCS。在JUN缺乏的小鼠中，神经再生受到损害。为了与糖尿病患者受损的轴突再生保持一致，我们发现，带有改变SC代谢的突变的小鼠无法有效地促进神经再生。最近，我们研究了OGT-SCKO小鼠缺乏SC表达O-GlcNAc转移酶(OGT)的特征，OGT是一种催化O-GlcNAc部分与蛋白质在丝氨酸和苏氨酸残基上加成的酶。OGT活性受葡萄糖通过己糖胺生物合成途径的流量调节，因此它是一个传感器，聚集有关葡萄糖代谢的信息并将其传递到细胞生理变化中。值得注意的是，O-GlcN酰化异常与糖尿病、癌症和神经退行性疾病有关。在干细胞中缺乏O-GlcN酰化的小鼠会发展成一种假性脱髓鞘神经病。OGT-SCKO坐骨神经表达谱显示许多AP-1靶点高表达。此外，我们还发现Jun的磷酸化和转录活性受O-GlcN酰化的调节。与JUN活性的异常一致，我们发现OGT的丢失导致再生/再髓鞘生成显著减少，表明SC损伤反应受到 新陈代谢。这些结果使我们假设糖尿病患者神经再生不良，并有可能 神经病本身是由于代谢异常对代谢性疾病的发生、功能和/或 停止SC损伤反应。为了追寻这一假设，我们提出了三个目标：1)调查 代谢影响SC损伤反应；2)探讨O-GlcN酰化在调节Jun中的作用 3)确定AP-1伙伴和其他调节因子在SC损伤反应中的作用。穿过 这些研究，我们希望表明，针对雪旺细胞及其修复功能的治疗将是有用的 治疗神经病和创伤性神经损伤。

Diabetic peripheral neuropathy is an increasingly common disorder that affects up to 25% of diabetic patients. The pathological underpinning of diabetic neuropathy is the loss of axonal integrity and function. In addition to axonal loss, impaired nerve fiber regeneration after injury is commonplace in diabetics and is recapitulated in rodent diabetic models. Axonal injury triggers a dramatic reprogramming of the Schwann cells (SCs) surrounding the damaged axon that culminates in the adoption of a `repair SC' phenotype. The repair SC promotes axon/myelin breakdown and disposal, attracts macrophages, produces neurotrophic factors, and elaborates adhesive molecules. Upon contact with the regenerating axon, it transforms back into a differentiated SC to ensure remyelination or Remak bundle formation. The primary regulator of this repair SC transition is the transcription factor c-Jun, which is rapidly activated after injury in SCs surrounding damaged axons. In Jun-deficient mice, nerve regeneration is impaired. In keeping with the impaired axon regeneration in diabetes, we find that mice with mutations that alter SC metabolism fail to effectively promote nerve regeneration. Most recently, we characterized OGT-SCKO mice that lack SC expression of O-GlcNAc transferase (OGT), the enzyme that catalyzes addition of O-GlcNAc moieties to proteins at Ser and Thr residues. OGT activity is regulated by the flux of glucose through the hexosamine biosynthetic pathway, thus it serves as a sensor that aggregates information regarding glucose metabolism and transmits it into changes in cell physiology. Notably, abnormal O-GlcNAcylation has been implicated in diabetes, cancer, and neurodegenerative diseases. Mice lacking O-GlcNAcylation in SCs develop a tomaculous demyelinating neuropathy. Expression profiling of OGT-SCKO sciatic nerve revealed high expression of many AP-1 targets. Moreover, we find that JUN phosphorylation and transcriptional activity are regulated by O-GlcNAcylation. In keeping with abnormalities in JUN activity, we find that loss of OGT leads to a substantial decrease in regeneration/remyelination, indicating that the SC injury response is modulated by metabolism. These results lead us to hypothesize that poor nerve regeneration in diabetes, and potentially the neuropathy itself, is caused by the impact of abnormal metabolism on the generation, function, and/or cessation of the SC injury response. To pursue this hypothesis we propose three aims: 1) To investigate how metabolism impacts the SC injury response; 2) To investigate the role of O-GlcNAcylation in regulating JUN activity; and 3) To determine the role of AP-1 partners and other regulators in the SC injury response. Through these studies, we hope to show that therapies targeting Schwann cells and their repair functions will be useful in treating neuropathy and traumatic nerve injury.