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：周围神经病是一种越来越常见的疾病，影响高达25% 糖尿病患者和35-40%的老年人。慢性周围神经病的病理基础 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，轴突丢失是 伴随着损伤后神经纤维再生的受损；在啮齿动物模型中再现的一种状态。 轴突损伤引发受损轴突周围雪旺细胞(SCs)的戏剧性重新编程 这最终导致了“修复SC”表型的采用。修复SC促进轴突/髓鞘的破坏 和处置，吸引巨噬细胞，并产生神经营养因子。在与再生装置接触时 轴突，它转化回分化的SC，以确保重新髓鞘形成或Remak束形成。这个 这种向修复SC转变的主要调节因子是转录因子Jun，它被迅速激活 损伤后损伤轴突周围的SCs。在JUN缺乏的小鼠中，神经再生受到损害。 与糖尿病和老年动物轴突再生受损的情况一致，我们发现患有糖尿病和老年动物的老鼠 改变SC代谢的突变不能有效地促进神经再生。最近，我们 缺乏O-GlcNAc转移酶(OGT)SC表达的OGT-SCKO小鼠的特征 催化蛋白质在丝氨酸和苏氨酸残基上的O-GlcNAc部分的加成。OGT活动受 葡萄糖通过己糖胺生物合成途径的流量，因此它是一个聚集的传感器 有关葡萄糖代谢的信息，并将其传递到细胞生理学的变化中。值得注意的是，异常 O-GlcN酰化与糖尿病、癌症和神经退行性疾病有关。小鼠缺乏O- 干细胞中的GlcN酰化形成一种假性脱髓鞘神经病。OGT-SCKO的表达谱分析 坐骨神经多个AP-1靶点呈高表达。此外，我们还发现Jun的磷酸化和 转录活性受O-GlcN酰化调控。根据Jun活动的异常情况，我们发现 OGT的丢失导致再生/再髓鞘形成显著减少，表明SC损伤 反应受到新陈代谢的调节。这些结果让我们假设，神经再生不良，而且 潜在的神经病变本身，在糖尿病和老年人中是由异常的影响引起的 代谢通过对Jun的直接作用影响SC损伤反应的产生、功能和/或停止 活动。为了推进这一假说，我们提出了三个目标：1)研究新陈代谢如何影响SC 损伤反应；2)研究O-GlcN酰化在调节JUN活性中的作用；3)确定 AP-1合作伙伴和其他调节因子在SC损伤反应中的作用。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在治疗外周血细胞方面有用 神经病和创伤性神经损伤。