Epigenetic Regulation of Peripheral Nerve Myelination

周围神经髓鞘形成的表观遗传调控

• 批准号: 8508095
• 负责人: John P Svaren
• 金额: $ 33.65万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508095
• 关键词: Action Potentials; Affect; Aging; Axon; Cells; ChIP-seq; Charcot-Marie-Tooth Disease; Chromatin Remodeling Factor; Communicable Diseases; Complex; DNA Methylation; Data; Deacetylase; Development; Diabetic Neuropathies; Disease; Down-Regulation; Effectiveness; Ensure; Epigenetic Process; Gene Activation; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Goals; Hereditary Disease; Histone H3; Histones; Inflammation; Injury; Laboratories; Maintenance; Maps; Methylation; Modification; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Nerve; Nervous System Trauma; Nervous system structure; Neurons; Nucleosomes; Pathway interactions; Peripheral; Peripheral Nerves; Peripheral Nervous System; Polycomb; Process; Recovery; Regulation; Repression; Research; Role; Schwann Cells; Sequence Analysis; Site; Techniques; Testing; Time; Transcription factor genes; Transcriptional Regulation; base; chromatin immunoprecipitation; chromatin modification; epigenetic marker; gene repression; genome-wide; histone modification; in vivo; insight; myelination; nerve injury; nervous system development; nervous system disorder; normal aging; programs; remyelination; research study; response; response to injury; transcription factor

DESCRIPTION (provided by applicant): 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 genetic control of myelination has been a major focus of research, and critical transcription factors and their target gene networks have begun to be elucidated. Interestingly, recent studies have demonstrated that formation of myelin-and it longs term maintenance-depends upon not only gene activation, but also downregulation of genes that inhibit myelin formation. Although substantial progress has been made to identify gene expression changes that coordinate myelination, there have been relatively few studies examining the chromatin modifications required for myelination. For example, myelin maintenance depends upon a program of gene repression, but practically nothing is known regarding the role of histone/DNA methylation in this vital aspect of myelination. The long term objective of our laboratory is to elucidate an integrated mechanism of myelination based on critical genetic and epigenetic switches required for myelin formation and maintenance. Specifically, this proposal focuses on testing the involvement of the polycomb epigenetic pathway in peripheral nerve myelination. Chromatin immunoprecipitation analyses will be used to determine the developmental regulation of epigenetic markers in response to injury and aging. The analysis will focus on epigenetic changes that occur in gene loci that are repressed during the myelination process, and test for the first time the involvement of the polycomb pathway in formation and long term maintenance of myelin. Finally, this proposal also takes advantage of several unique aspects of peripheral nerve, which facilitate the epigenetic analysis that we have proposed here.

描述（由申请人提供）：神经系统中轴突的髓鞘化不仅对于传导动作电位的传导至关重要，而且对于提供热带支持以确保神经元在中心神经系统和周围神经系统中的长期存活至关重要。髓磷脂疾病是神经疾病的主要原因，可能是由遗传疾病，传染病和炎症引起的。因此，了解控制髓鞘细胞中基因表达模式的途径不仅是阐明发育途径的关键步骤，而且还可以深入了解神经损伤后的再髓层可以加速的手段。髓鞘化的遗传控制一直是研究的主要重点，关键的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，髓磷脂的形成不仅依赖于基因激活，而且还依赖于抑制髓磷脂形成的基因的下调。 尽管已经取得了实质性的进展来识别协调髓鞘形成的基因表达变化，但是研究了相对较少的研究，研究了髓鞘形成所需的染色质修饰。例如，髓磷脂的维持取决于基因抑制程序，但几乎没有关于组蛋白/DNA甲基化在这一至关重要的髓鞘方面的作用。我们实验室的长期目标是基于髓磷脂形成和维持所需的关键遗传和表观遗传学开关来阐明髓鞘化的综合机制。具体而言，该提案的重点是测试多肉液表观遗传途径在周围神经髓鞘中的参与。染色质免疫沉淀分析将用于确定响应损伤和衰老的表观遗传标记的发育调控。该分析将集中在基因基因座中发生的表观遗传变化，这些变化在髓鞘化过程中被抑制，并首次测试PolyComb途径参与髓磷脂的形成和长期维持。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出的表观遗传分析。