Epigenetic Regulation of Nerve Injury

神经损伤的表观遗传调控

• 批准号: 9396615
• 负责人: John P Svaren
• 金额: $ 34.2万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396615
• 关键词: Action Potentials; Aging; Axon; Binding; Cells; Chromatin; Chronic; Communicable Diseases; Complex; Coupled; Data; Data Set; Development; Diabetic Neuropathies; Disease; Enhancers; Ensure; Enzymes; Epigenetic Process; Excision; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Goals; Hereditary Disease; Histones; Inflammation; Injury; JUN gene; Knock-out; Laboratories; Light; Mediating; Metabolic; MicroRNAs; Modeling; Myelin; Myelin Sheath; Natural regeneration; Nerve; Nerve Regeneration; Nerve compression syndrome; Nervous System Trauma; Nervous system structure; Neural Crest; Neurons; Pathway interactions; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Play; Polycomb; Process; Recovery; Recruitment Activity; Regenerative response; Regulation; Reporter Genes; Repression; Role; SHH gene; Schwann Cells; Testing; Time; Work; axon regeneration; base; chemotherapy; chromatin immunoprecipitation; chromatin modification; demethylation; epigenetic regulation; epigenomics; histone demethylase; histone methylation; histone modification; injured; insight; myelination; nerve injury; nervous system development; nervous system disorder; neurodevelopment; neurotrophic factor; novel; peripheral nerve regeneration; programs; regenerative; remyelination; repaired; response; response to injury; transcription factor

Abstract Myelination of axons in the nervous system is critical for not only conduction of action potentials, but also for providing tropic support to ensure long term survival of neurons in both the central and peripheral nervous systems. Myelin disorders are a major cause of neurological disease, and can be caused by genetic disorders, infectious disease, and inflammation. Therefore, understanding the pathways that control gene expression patterns in myelinating cells is a critical step in not only elucidating developmental pathways, but also to provide insight into means by which remyelination after nerve injury can be accelerated. The peripheral nervous system has substantial plasticity in being able to regenerate after nerve injury, and critical transcription factors and their target gene networks have begun to be elucidated. Interestingly, recent studies have demonstrated that Schwann cell reprogramming to a new differentiated state is a critical and rate limiting factor in peripheral nerve regeneration. Although substantial progress has been made to identify gene expression changes that occur after injury, there have been relatively few studies examining the chromatin modifications required for Schwann cell reprogramming to the injured state. The long term objective of our laboratory is to elucidate an integrated mechanism of Schwann cell reprogramming after nerve injury based on critical microRNA and epigenomic switches that we have identified. Specifically, this proposal focuses on testing how reversal of the polycomb pathway is required for Schwann cell responses to peripheral nerve injury. Chromatin immunoprecipitation analyses will focus on epigenetic changes that occur during nerve injury, and test for the first time the involvement of histone demethylases in nerve injury responses. Finally, this proposal also takes advantage of several unique aspects of peripheral nerve, which facilitate the epigenomic analysis that we have proposed here.

摘要 神经系统中轴突的髓鞘化不仅对行为的传导至关重要， 潜力，但也提供热带支持，以确保长期生存的神经元在这两个 中枢和外周神经系统。髓鞘疾病是神经系统疾病的主要原因。 疾病，并且可以由遗传疾病、传染病和炎症引起。 因此，了解控制髓鞘形成中基因表达模式的途径， 细胞不仅是阐明发育途径的关键一步， 从而加速神经损伤后髓鞘再生。周围神经 系统在神经损伤后能够再生方面具有很大的可塑性， 转录因子和它们的靶基因网络已经开始被阐明。有趣的是， 最近的研究表明，雪旺细胞重编程为新的分化的 状态是周围神经再生的关键和速率限制因素。 尽管在鉴定基因表达变化方面已经取得了实质性进展， 发生损伤后，有相对较少的研究检查染色质修饰 雪旺氏细胞重编程到受损状态所需的。我们的长远目标 实验室旨在阐明神经损伤后雪旺细胞重编程的综合机制， 损伤的关键microRNA和表观基因组开关，我们已经确定。具体地说， 这项提案的重点是测试如何逆转多梳途径是需要雪旺氏 细胞对周围神经损伤的反应。染色质免疫沉淀分析将集中在 在神经损伤期间发生的表观遗传变化，并首次测试了 组蛋白去甲基化酶在神经损伤反应中的作用最后，该提案还利用了 周围神经的几个独特的方面，这有利于表观基因组分析，我们 在这里求婚。