Metabolic Regulation of the Schwann Cell Injury Response

糖尿病周围神经病变是一种日益常见的疾病，影响多达25%的糖尿病患者。糖尿病神经病变的病理基础是轴突完整性和功能的丧失。除了轴突损失之外，损伤后受损的神经纤维再生在糖尿病患者中是常见的，并且在啮齿动物糖尿病模型中重现。轴突损伤触发了受损轴突周围的雪旺细胞（SC）的戏剧性重编程，最终采用“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，并阐述粘附分子。在与再生轴突接触时，它转化回分化的SC以确保髓鞘再生或Remak束形成。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， 受损轴突周围的SC。在Jun-deficient小鼠中，神经再生受损。 与糖尿病中受损的轴突再生一致，我们发现具有改变SC代谢的突变的小鼠不能有效地促进神经再生。最近，我们表征了缺乏O-GlcNAc转移酶（OGT）的SC表达的OGT-SCKO小鼠，O-GlcNAc转移酶（OGT）是催化O-GlcNAc部分在Ser和Thr残基处添加到蛋白质的酶。OGT活性受葡萄糖通过己糖胺生物合成途径的流量调节，因此其充当聚集关于葡萄糖代谢的信息并将其传递到细胞生理学变化中的传感器。值得注意的是，异常的O-GlcNAc化与糖尿病、癌症和神经退行性疾病有关。在SC中缺乏O-GlcNAc化的小鼠发展成绒毛膜脱髓鞘性神经病。OGT-SCKO坐骨神经的表达谱揭示了许多AP-1靶标的高表达。此外，我们发现JUN磷酸化和转录活性受O-GlcNAc化的调节。与JUN活性的异常一致，我们发现OGT的缺失导致再生/髓鞘再生的显著减少，表明SC损伤反应受到以下因素的调节： 新陈代谢.这些结果使我们假设，糖尿病患者的神经再生不良， 神经病本身是由异常代谢对神经系统的产生、功能和/或功能的影响引起的。 停止SC损伤反应。为了实现这一假设，我们提出了三个目标：1）调查如何 2）研究O-GlcNAc化在JUN调节中的作用 活性;和3）确定AP-1伴侣和其他调节剂在SC损伤反应中的作用。通过 通过这些研究，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.