Epigenetic Regulation of Nerve Injury

神经损伤的表观遗传调控

• 批准号: 10207795
• 负责人: John P Svaren
• 金额: $ 32.9万
• 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/10207795
• 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; Genes; Genetic Diseases; Genetic Transcription; Goals; 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; 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 damage; nerve injury; nerve repair; nervous system development; nervous system disorder; neurodevelopment; neurotrophic factor; novel; peripheral nerve regeneration; programs; recruit; regeneration potential; remyelination; repaired; response; response to injury; severe 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.

抽象的 神经系统中轴突的髓鞘化不仅对于行动的传导至关重要 潜力，而且还提供热带支持，以确保神经元的长期存活 中枢和周围神经系统。髓磷脂紊乱是神经系统疾病的主要原因 疾病，可由遗传性疾病、传染病和炎症引起。 因此，了解控制髓鞘形成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，而且也是提供洞察力的关键一步 成为加速神经损伤后髓鞘再生的方法。周围神经 系统在神经损伤后能够再生具有很大的可塑性，并且至关重要 转录因子及其靶基因网络已开始被阐明。有趣的是， 最近的研究表明施万细胞重编程为新的分化细胞 状态是周围神经再生的关键和速率限制因素。 尽管在识别基因表达变化方面已经取得了实质性进展 发生在损伤后，检查染色质修饰的研究相对较少 施万细胞重编程至损伤状态所需的。我们的长期目标 实验室的目标是阐明神经损伤后雪旺细胞重编程的整合机制 基于我们已经确定的关键 microRNA 和表观基因组开关的损伤。具体来说， 该提案的重点是测试 Schwann 需要如何逆转多梳途径 细胞对周围神经损伤的反应。染色质免疫沉淀分析将重点关注 神经损伤过程中发生的表观遗传变化，并首次测试了神经损伤的参与 神经损伤反应中的组蛋白去甲基化酶。最后，该提案还利用了 周围神经的几个独特方面，有助于我们进行表观基因组分析 已在这里提出。