Metabolic Regulation of the Schwann Cell Injury Response

雪旺细胞损伤反应的代谢调节

• 批准号: 9527211
• 负责人: JEFFREY D MILBRANDT
• 金额: $ 47.73万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9527211
• 关键词: Adhesives; Adoption; Affect; Axon; Back; Binding Proteins; Biological Assay; Cell physiology; Cells; Cellular Metabolic Process; Complex; Diabetes Mellitus; Diabetic Neuropathies; Diabetic mouse; Dimerization; Disease; Ensure; Enzymes; Excision; FOS Protein; Gene Expression; Generations; Genetic Transcription; Glucose; Health; Heterodimerization; Hexosamines; Human; Impairment; Injury; JUN gene; Lead; Lentivirus Infections; Link; MAPK8 gene; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Modification; Molecular; Molecular Profiling; Mus; Mutagenesis; Mutant Strains Mice; Mutation; Myelin; Names; Natural regeneration; Nerve; Nerve Fibers; Nerve Regeneration; Neurodegenerative Disorders; Neuropathy; Nutrient; O-GlcNAc transferase; Pathologic; Pathology; Pathway interactions; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phenotype; Phosphorylation; Process; Proteins; Recovery of Function; Regulation; Research; Rodent; Role; STK11 gene; Schwann Cells; Tamoxifen; Testing; Transcription Factor AP-1; Traumatic Nerve Injury; axon injury; axon regeneration; axonal degeneration; db/db mouse; diabetic; diabetic patient; diabetic rat; dimer; experimental study; gain of function; glucose metabolism; in vivo; injured; jun Oncogene; macrophage; mouse model; mutant; myelination; nerve injury; neurotrophic factor; programs; protein function; regenerative; remyelination; repaired; response to injury; sciatic nerve; sensor; targeted treatment; transcription factor

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.

糖尿病周围神经病是一种日益常见的疾病，可影响多达25％的糖尿病患者。糖尿病神经病的病理基础是轴突完整性和功能的丧失。除轴突损失外，受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被概括。轴突损伤触发了围绕受损的轴突周围的Schwann细胞（SC）的戏剧性重编程，该轴突在采用“修复SC”表型中最终导致。维修SC可促进轴突/髓磷脂的分解和处置，吸引巨噬细胞，产生神经营养因子并详细说明粘附分子。与再生轴突接触后，它将转换为差异化的SC，以确保remerryalination或Remak Bundle形成。该修复SC转换的主要调节剂是转录因子C-JUN，该因子在损伤后迅速激活 围绕受损轴突的SC。在缺乏的小鼠中，神经再生受到损害。 与糖尿病中轴突再生受损相符，我们发现具有改变SC代谢的突变的小鼠无法有效促进神经再生。最近，我们表征了缺乏O-GlCNAC转移酶（OGT）SC表达的OGT-SCKO小鼠，该酶是将O-GlCNAC部分催化为在Ser和THR残基处添加到蛋白质中的酶。 OGT活性由葡萄糖通过己糖胺生物合成途径的通量调节，因此它是一种传感器，可以汇总有关葡萄糖代谢的信息，并将其传输到细胞生理学的变化中。值得注意的是，异常的O-Glcnacylation与糖尿病，癌症和神经退行性疾病有关。在SC中缺乏O-Glcnacylation的小鼠会形成一个整洁的脱髓鞘神经病。 OGT-SCKO坐骨神经的表达分析显示许多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-Glcnacylation的调节。为了与JUN活动中的异常保持一致，我们发现OGT的丧失导致再生/再生的大幅下降，表明SC损伤反应受 代谢。这些结果使我们假设糖尿病的神经再生不良，可能是 神经病本身是由异常代谢对产生，功能和/或的影响引起的 停止SC损伤反应。为了提出这一假设，我们提出了三个目标：1）调查如何 代谢会影响SC损伤反应； 2）研究O-Glcnacylation在调节Jun中的作用 活动; 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 这些研究，我们希望证明针对雪旺细胞及其修复功能的疗法将是有用的 治疗神经病和创伤性神经损伤。