MECHANISMS OF CHROMATIN REMODELING PROMOTING AXON REGENERATION

染色质重塑促进轴突再生的机制

• 批准号: 9237053
• 负责人: Valeria Cavalli
• 金额: $ 33.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237053
• 关键词: Acetylation; Acute; Affect; Afferent Neurons; Axon; Back; Breathing; Calcineurin; Calcium; Calcium Oscillations; Cell Line; Cells; Chromatin; Competence; EP300 gene; Epigenetic Process; Event; Exhibits; Failure; Future; Gene Expression; Gene Targeting; Genes; Goals; Grant; Growth; HDAC5 gene; Histone Acetylation; Histones; Human; Hypoxia; Hypoxia Inducible Factor; Individual; Injury; JUN gene; Laboratories; Link; Mediating; Medical; Modeling; Molecular; Mus; Natural regeneration; Nerve Crush; Nervous System Physiology; Neuraxis; Neurobiology; Neuronal Hypoxia; Neurons; Nuclear; Nuclear Import; Optic Nerve; Optic Nerve Injuries; Oxygen; Pathway interactions; Patients; Peripheral; Phosphorylation; Play; Problem Solving; Recovery; Recovery of Function; Regenerative response; Reporting; Retinal Ganglion Cells; Role; STAT3 gene; Signal Pathway; Signal Transduction; Site; Spinal Ganglia; Testing; Time; Transcriptional Activation; Transferase; Work; abstracting; axon injury; axon regeneration; base; central nervous system injury; chromatin modification; chromatin remodeling; disability; epigenetic regulation; filamin; histone modification; injured; insight; novel; programs; regenerative; relating to nervous system; repaired; research study; response; response to injury; sciatic nerve; success; transcription factor; treatment strategy

ABSTRACT Lack of robust axonal regeneration represents a major barrier to functional recovery following injury to neurons within the central nervous system (CNS). In contrast, peripheral neurons can regenerate after injury. Activation of a pro-regenerative growth program in peripheral neurons relies on the expression of regeneration-associated genes (RAGs) that allow for robust axonal re-growth. Although several genes have been identified for their pro-regenerative influence, individual gene based approaches have yielded limited success in axon regeneration, illustrating that manipulation of individual RAGs is unlikely to be sufficient to stimulate robust long-distance axon regeneration in the injured CNS. Therefore, understanding how a large ensemble of RAGs can be simultaneously activated after injury could reveal strategies to initiate the transcriptional pro-regenerative program. Epigenetic regulations, which include modification of the chromatin, affect combinations of multiple genes and hence represent ideal strategies to promote neural repair. Our goal is to gain new insights into the molecular events that regulate chromatin function in response to injury in peripheral neurons, and identify potential targets for future treatment of CNS injuries We previously demonstrated that axon injury elicits an epigenetic switch stimulating the regenerative competence of sensory neurons. Specifically, we discovered that calcium wave back-propagating from the site of axonal injury increases histone acetylation levels, stimulating the regenerative competence of sensory neuron. This work demonstrates a link between axon injury and chromatin remodeling and suggests that a coordinated pro-regenerative program is initiated by changes in the epigenetic landscape. In our recent studies, we identified hypoxia-inducible factor 1α (HIF-1α) as an important factor regulating axon regeneration via epigenetic as well as transcriptional regulatory mechanisms. We found that HIF-1α is required in injured sensory neurons to increase histone acetylation levels, to stimulate the expression of pro- regenerative genes and to promote axon regeneration. In mice breathing repeatedly low oxygen levels for brief periods (i.e., acute intermittent hypoxia, AIH) we observed increased levels of HIF-1α and enhanced axon regeneration in sensory neurons. However, the signaling pathways in normoxic conditions regulating HIF-1α accumulation and the precise mechanisms by which HIF-1α regulates chromatin in injured neurons remain elusive. Here we propose to uncover the molecular mechanisms controlling HIF-1α stability and activity following injury and to establish its specific roles in chromatin remodeling in injured neurons. We will also test if AIH can recapitulate at least in part the epigenetic changes elicited by peripheral axon injury and activate a pro-regenerative program in both peripheral and central neurons. This proposal has the potential to provide further rationale for the improvement of AIH-based treatment strategies for human patients. .

抽象的 缺乏强大的轴突再生是损伤后功能恢复的主要障碍 中枢神经系统（CNS）内的神经元。相反，周围神经元在损伤后可以再生。 周围神经元中促再生生长程序的激活依赖于以下物质的表达： 再生相关基因（RAG）允许强健的轴突再生长。虽然有几个基因 已确定其促再生影响，基于个体基因的方法已取得有限的成果 轴突再生的成功，说明对单个 RAG 的操纵不太可能足以 刺激受损中枢神经系统的强健长距离轴突再生。因此，了解如何大 RAGs 集合可以在受伤后同时激活，这可能揭示启动 转录促再生程序。表观遗传调控，包括染色质的修饰， 影响多个基因的组合，因此代表了促进神经修复的理想策略。我们的目标 的目的是获得对调节染色质功能以响应损伤的分子事件的新见解 周围神经元，并确定未来治疗中枢神经系统损伤的潜在靶点 我们之前证明轴突损伤会引发表观遗传开关，刺激再生 感觉神经元的能力。具体来说，我们发现钙波从 轴突损伤部位增加组蛋白乙酰化水平，刺激感觉再生能力 神经元。这项工作证明了轴突损伤和染色质重塑之间的联系，并表明 协调的促再生程序是由表观遗传景观的变化启动的。在我们最近的 研究中，我们确定缺氧诱导因子 1α (HIF-1α) 是调节轴突的重要因子 通过表观遗传和转录调控机制再生。我们发现HIF-1α是 受伤的感觉神经元需要增加组蛋白乙酰化水平，刺激前体的表达 再生基因并促进轴突再生。小鼠反复呼吸低氧水平 短期内（即急性间歇性缺氧，AIH），我们观察到 HIF-1α 水平升高，并且增强 感觉神经元的轴突再生。然而，常氧条件下调节的信号通路 HIF-1α 积累以及 HIF-1α 调节受损神经元染色质的精确机制 仍然难以捉摸。在这里，我们建议揭示控制 HIF-1α 稳定性的分子机制和 损伤后的活性并确定其在受损神经元染色质重塑中的特定作用。我们将 还测试 AIH 是否可以至少部分重现外周轴突损伤引起的表观遗传变化，以及 激活外周和中枢神经元的促再生程序。该提案有潜力 为改进人类患者基于 AIH 的治疗策略提供进一步的理论依据。 。