MECHANISMS OF CHROMATIN REMODELING PROMOTING AXON REGENERATION

染色质重塑促进轴突再生的机制

• 批准号: 9328185
• 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/9328185
• 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; Genetic Transcription; Goals; Grant; Growth; HDAC5 gene; Histone Acetylation; Histone Deacetylase; 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 of Function; Regenerative response; Reporting; Retinal Ganglion Cells; Role; STAT3 gene; Signal Pathway; Signal Transduction; Site; Spinal Ganglia; Testing; Time; Transcriptional Activation; Transferase; Work; axon injury; axon regeneration; base; central nervous system injury; chromatin modification; chromatin remodeling; disability; epigenetic regulation; experimental study; filamin; histone modification; injured; insight; neurological recovery; novel; programs; regenerative; relating to nervous system; repaired; 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 缺乏健壮的轴突再生代表了受伤后功能恢复的主要障碍 中枢神经系统（CNS）中的神经元。相反，受伤后周围神经元可以再生。 激活周围神经元中的促增长增长计划取决于表达 再生相关基因（RAGS），可实现稳健的轴突重新生长。虽然几个基因有 因其促进影响而被鉴定出来，基于基因的方法产生了有限 在轴突再生方面的成功，说明对单个抹布的操纵不可能足够 刺激受伤的中枢神经系统中强大的长距离轴突再生。因此，了解一个大型 抹布的合奏可以在受伤后简单地激活，可以揭示策略来发起 转录亲获得计划。表观遗传法规，其中包括染色质的修饰， 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 是为了获得调节染色质功能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标 我们先前证明了轴突损伤引起的表观遗传开关刺激了再生 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，刺激感觉的再生能力 神经元。这项工作证明了轴突损伤与染色质重塑之间的联系，并建议 协调的亲获得计划是由表观遗传景观的变化启动的。在我们的最新消息中 研究，我们将低氧诱导因子1α（HIF-1α）确定为调节轴突的重要因子 通过表观遗传和转录调节机制再生。我们发现HIF-1α是 在受伤的感觉神经元中需要增加组蛋白乙酰化水平，以刺激促进的表达 再生基因并促进轴突再生。在呼吸反复低的氧气水平中 短期（即急性间歇性缺氧，AIH），我们观察到HIF-1α的水平增加，并增强了 感觉神经元中的轴突再生。但是，调节常氧条件下的信号通路 HIF-1α的积累和HIF-1α调节受伤神经元中染色质的精确机制 保持难以捉摸。在这里，我们建议发现控制HIF-1α稳定性和的分子机制 损伤后的活性并确定其在受伤神经元中染色质重塑中的特定作用。我们将 还测试AIH是否至少可以在某种程度上概括。 激活外围和中央神经元中的亲再生程序。该提议有可能 为改善人类患者的基于AIH的治疗策略提供了进一步的理由。 。