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。周围神经病变的病理基础 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，轴突损失是 伴有损伤后神经纤维再生受损；啮齿动物模型中重现的状态。 轴突损伤会引发受损轴突周围雪旺细胞 (SC) 的剧烈重编程 最终形成“修复 SC”表型。修复 SC 促进轴突/髓磷脂分解 和处理，吸引巨噬细胞，并产生神经营养因子。与再生体接触后 轴突后，它会转变回分化的 SC，以确保髓鞘再生或 Remak 束形成。这 向修复 SC 转变的主要调节因子是转录因子 JUN，它会被快速激活 受损轴突周围的 SC 受伤后。在 Jun 缺陷小鼠中，神经再生受到损害。 与糖尿病和老年动物的轴突再生受损相一致，我们发现患有糖尿病的小鼠 改变 SC 代谢的突变无法有效促进神经再生。最近，我们 OGT-SCKO 小鼠的特征是缺乏 O-GlcNAc 转移酶 (OGT) 的 SC 表达，该酶 催化 O-GlcNAc 部分添加到蛋白质的 Ser 和 Thr 残基上。 OGT 活动受监管 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转化为细胞生理学的变化。值得注意的是，异常 O-GlcNAc 酰化与糖尿病、癌症和神经退行性疾病有关。缺乏O-的小鼠 SC 中的 GlcNAc 化会导致斑块性脱髓鞘性神经病。 OGT-SCKO 的表达谱 坐骨神经显示许多 AP-1 靶点的高表达。此外，我们发现 JUN 磷酸化和 转录活性受 O-GlcNAc 酰化调节。与 JUN 活动的异常情况一致，我们发现 OGT 的丧失导致再生/髓鞘再生的显着减少，表明 SC 损伤 反应受新陈代谢调节。这些结果使我们推测神经再生不良，并且 糖尿病和老年人的神经病变本身可能是由异常的影响引起的 通过对 JUN 的直接影响，代谢对 SC 损伤反应的产生、功能和/或停止的影响 活动。为了实现这一假设，我们提出三个目标：1) 研究新陈代谢如何影响 SC 伤害反应； 2) 探讨O-GlcNAcylation在调节JUN活性中的作用； 3) 确定 AP-1 伙伴和其他调节因子在 SC 损伤反应中的作用。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疗法将有助于治疗外周血 神经病变和创伤性神经损伤。