Metabolic Regulation of the Schwann Cell Injury Response

雪旺细胞损伤反应的代谢调节

基本信息

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
项目类别：
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

项目摘要

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.

糖尿病周围神经病变是一种越来越常见的疾病，影响高达 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，损伤后神经纤维再生受损在糖尿病患者中也很常见，并且在啮齿类糖尿病模型中也有重现。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/髓磷脂的分解和处理，吸引巨噬细胞，产生神经营养因子，并精心制作粘附分子。在与再生轴突接触后，它会变回分化的 SC，以确保髓鞘再生或 Remak 束的形成。这种修复 SC 转变的主要调节因子是转录因子 c-Jun，它在损伤后迅速激活。 SC 围绕受损的轴突。在 Jun 缺陷小鼠中，神经再生受到损害。与糖尿病中轴突再生受损相一致，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，我们对 OGT-SCKO 小鼠进行了表征，其缺乏 O-GlcNAc 转移酶 (OGT) 的 SC 表达，OGT 是催化 O-GlcNAc 部分在 Ser 和 Thr 残基上添加到蛋白质中的酶。 OGT 活性受到己糖胺生物合成途径中葡萄糖流量的调节，因此它可以作为传感器，聚集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，异常的 O-GlcNAc 酰化与糖尿病、癌症和神经退行性疾病有关。 SC 中缺乏 O-GlcNAc 酰化的小鼠会出现斑块性脱髓鞘性神经病。 OGT-SCKO 坐骨神经的表达谱显示许多 AP-1 靶标的高表达。此外，我们发现JUN磷酸化和转录活性受到O-GlcNAc糖基化的调节。与 JUN 活性的异常一致，我们发现 OGT 的缺失会导致再生/髓鞘再生的大幅减少，表明 SC 损伤反应受到以下因素的调节：代谢。这些结果使我们推测糖尿病患者的神经再生不良，并且可能导致神经病本身是由代谢异常对生成、功能和/或 SC损伤反应的停止。为了实现这一假设，我们提出了三个目标：1）研究如何新陈代谢影响 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 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是有用的用于治疗神经病和创伤性神经损伤。