Epigenetic Regulation of Nerve Injury

神经损伤的表观遗传调控

基本信息

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
项目类别：
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

项目摘要

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传导作用至关重要潜力，但也提供热带支持以确保神经元的长期生存中央和周围神经系统。髓磷脂疾病是神经系统的主要原因疾病，可能是由遗传疾病，传染病和炎症引起的。因此，了解控制基因表达模式在髓鞘中的途径细胞不仅是阐明发育途径的关键步骤，而且是提供洞察力进入神经损伤后的再生的手段。周围神经系统在神经损伤后能够再生和关键转录因子及其靶基因网络已经开始阐明。有趣的是，最近的研究表明，Schwann细胞重编程为新的分化状态是周围神经再生的关键和速率限制因素。尽管已经取得了重大进展来确定基因表达变化受伤后发生，研究染色质修饰的研究相对较少 Schwann细胞重编程为受伤状态所需的。我们的长期目标实验室是为了阐明神经后的schwann细胞重编程的集成机制我们已经确定的基于关键的microRNA和表观基因组开关的伤害。具体来说，该建议重点是测试Schwann需要如何逆转Polycomb途径细胞对周围神经损伤的反应。染色质免疫沉淀分析将集中于神经损伤期间发生的表观遗传变化，并首次测试神经损伤反应中的组蛋白去甲基酶。最后，该建议还利用了周围神经的几个独特方面，这有助于我们在这里提议。