Jun O-GlcNAcylation Regulates Schwann Cell Injury Response

Jun O-GlcNAcylation 调节雪旺细胞损伤反应

• 批准号: 9915989
• 负责人: JEFFREY D MILBRANDT
• 金额: $ 41.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915989
• 关键词: Adoption; Affect; Age; Animals; Axon; Back; Binding Proteins; Biological Assay; Cell physiology; Cells; Cellular Metabolic Process; Complex; Diabetes Mellitus; Diabetic mouse; Dimerization; Disease; Elderly; Ensure; Enzymes; Etiology; Event; Excision; Expression Profiling; FOS Protein; Gene Expression; Gene Expression Profiling; Generations; Genetic Transcription; Glucose; Health; Heterodimerization; Hexosamines; Impairment; Individual; Injury; Lead; Lentivirus Infections; Link; MAPK8 gene; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolism; Molecular; 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 Model; Role; STK11 gene; Schwann Cells; Tamoxifen; Testing; Transcription Factor AP-1; Traumatic Nerve Injury; aged; axon injury; axon regeneration; axonal degeneration; cell transformation; db/db mouse; diabetic; diabetic rat; 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

Project Summary/Abstract: Peripheral neuropathy is an increasingly common disorder that affects up to 25% of diabetics and 35-40% of elderly individuals. The pathological underpinning of peripheral neuropathy from any etiology is the loss of axonal integrity and function. In diabetics and the aged, the axonal loss is accompanied by impaired nerve fiber regeneration after injury; a state that is recapitulated in rodent 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, and produces neurotrophic factors. 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 transition to the repair SC is the transcription factor 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 diabetic and aged animals, 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, and potentially the neuropathy itself, in diabetic and aged individuals is caused by the impact of abnormal metabolism on the generation, function, and/or cessation of the SC injury response via direct effects on JUN activity. 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 peripheral neuropathy and traumatic nerve injury.

项目摘要/摘要：周围神经病是一种日益常见的疾病，影响高达25％ 糖尿病患者和35-40％的老年人。外周神经病的病理基础 任何病因都是轴突完整性和功能的丧失。在糖尿病患者和老年人中，轴突损失为 受伤后的神经纤维再生受损；在啮齿动物模型中概括的状态。 轴突损伤触发围绕受损的轴突周围的雪旺细胞（SC）的戏剧性重编程 这最终在采用“修复SC”表型中。维修SC促进轴突/髓磷脂故障 处置，吸引巨噬细胞，并产生神经营养因素。接触再生 轴突，它转换回差异化的SC，以确保remeryelation或Remak Bundle形成。这 该过渡到维修SC的主要调节因子是转录因子JUN，该因子迅速激活 在受损轴突周围的SC受伤后。在缺乏的小鼠中，神经再生受到损害。 与糖尿病和老年动物中轴突再生的受损相符，我们发现与 改变SC代谢的突变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）的SC表达的OGT-SCKO小鼠，该酶是 将O-GlCNAC部分催化为在Ser和THR残基处的蛋白质。 OGT活动受 葡萄糖通过己糖胺生物合成途径的通量，因此它充当聚集的传感器 有关葡萄糖代谢的信息，并将其传输到细胞生理的变化中。值得注意的是，异常 O-Glcnacylation与糖尿病，癌症和神经退行性疾病有关。缺乏o-的小鼠 SC中的glcnacylation会形成一个整洁的脱髓鞘神经病。 OGT-SCKO的表达分析 坐骨神经揭示了许多AP-1靶标的高表达。此外，我们发现Jun磷酸化和 转录活性通过O-Glcnacylation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 反应是由代谢调节的。这些结果使我们假设那种不良的神经再生，以及 在糖尿病和老年人中，神经病本身可能是由异常的影响引起的 通过直接影响JUN的生成，功能和/或停止对SC损伤反应的代谢 活动。为了提出这一假设，我们提出了三个目标：1）研究新陈代谢如何影响SC 伤害反应； 2）研究O-glcnacylation在调节JUN活动中的作用； 3）确定 AP-1合作伙伴和其他监管机构在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有助于治疗周围 神经病和创伤性神经损伤。