Multicellular Mechanisms Driving Axon Regeneration

驱动轴突再生的多细胞机制

• 批准号: 10406343
• 负责人: Valeria Cavalli
• 金额: $ 89.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-17 至 2029-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406343
• 关键词: Affect; Afferent Neurons; Automobile Driving; Axon; Biological Models; Cells; Chromatin; Environment; Epigenetic Process; Esthesia; Failure; Future; Genes; Genetic Transcription; Goals; Human; Individual; Lead; Molecular Conformation; Molecular Profiling; Mus; Natural regeneration; Nervous System Trauma; Neuraxis; Neurobiology; Neuroglia; Neurons; Optic Nerve; Optic Nerve Injuries; Pathway interactions; Peripheral; Physiology; Process; Recovery; Regenerative capacity; Regulation; Research; Sensory Ganglia; Site; Spinal cord injury; Vision; axon growth; axon injury; axon regeneration; base; cell type; central nervous system injury; disability; epigenomics; improved; injured; innovation; mouse model; nerve damage; nerve repair; neuronal cell body; novel; novel strategies; programs; regenerative; repaired; success; tool

ABSTRACT Permanent disabilities following central nervous system (CNS) injuries result from the failure of injured axons to re-build functional connections. There are currently no therapies to restore mobility and sensation following spinal cord injury or vision after optic nerve damage. The poor intrinsic regenerative capacity of mature CNS neurons is a major contributor to the regeneration failure and remains a major problem in neurobiology. In contrast, peripheral sensory neurons successfully switch to a regenerative state after axon injury. The long-term goal of my research program is to understand the multicellular mechanisms by which injured sensory neurons activate a pro-regenerative program and identify potential targets for future treatment of CNS injuries. Activation of an axon growth program relies in part on the expression of regeneration-associated genes. Because individual gene based approaches have yielded limited success in axon regeneration, we are focusing on epigenomic regulations, which affect globally, yet specifically a combination of multiple genes. Our goal is to uncover how the epigenetic landscape is re-organized in the context of axon injury to enable axon repair. These studies will incorporate cell-type specific epigenomic analyses to study the transcriptional and chromatin conformation changes elicited by peripheral and central axon injury. Axon regeneration is not cell autonomous and is influenced by the environment at the level of the axon injury site and at the level of the cell soma. We have recently discovered that satellite glial cells, the main type of glial cells in sensory ganglia respond to axon injury and contribute to the repair process. We propose to use powerful combinations of tools to pursue an innovative line of research aimed at dissecting the multicellular mechanisms orchestrating axon regeneration and build upon these findings to improve regeneration in CNS models. To achieve this goal, we will determine the intrinsic neuronal mechanisms controlling axon regeneration, focusing on epigenomics studies. We will elucidate the contribution of the microenvironment surrounding neuronal soma to the axon regeneration process, including satellite glial cells and other non-neuronal cells. To determine if findings made in the mouse model system are predictive of human physiology, we will determine the molecular profile of human cells surrounding sensory neurons. Finally we propose to manipulate novel pathways we discover to improve regeneration in two CNS models, spinal cord injury and optic nerve injury. This proposal will use powerful combinations of tools to pursue an innovative line of research aimed at dissecting the multicellular mechanisms orchestrating axon regeneration and build upon these findings to improve regeneration in CNS models.

摘要 中枢神经系统（CNS）损伤后的永久性残疾是由于受伤者的失败造成的。 轴突来重建功能连接目前还没有恢复活动性和感觉的疗法 脊髓损伤或视神经损伤后的视力。差的内在再生能力， 成熟的中枢神经系统神经元是再生失败的主要原因， 神经生物学相比之下，外周感觉神经元在轴突再生后成功地切换到再生状态。 损伤我的研究计划的长期目标是了解多细胞机制， 受伤的感觉神经元激活了一个促再生程序，并确定了未来治疗的潜在目标 中枢神经系统损伤 轴突生长程序的激活部分依赖于再生相关基因的表达。 由于基于单个基因的方法在轴突再生方面取得了有限的成功， 专注于表观基因组调控，影响全球，但具体来说是多个基因的组合。我们 目标是揭示在轴突损伤的背景下表观遗传景观如何重组，以使轴突能够 修复.这些研究将结合细胞类型特异性表观基因组分析，以研究转录和 外周和中央轴突损伤引起的染色质构象变化。轴突再生不是细胞 并且在轴突损伤部位水平和细胞水平受环境影响 索马。我们最近发现，卫星神经胶质细胞，感觉神经节中的主要类型的神经胶质细胞， 对轴突损伤做出反应并促进修复过程。我们建议使用强大的工具组合 进行一项创新性的研究，旨在解剖协调轴突的多细胞机制， 再生，并建立在这些发现，以改善CNS模型的再生。为了实现这一目标，我们 将确定控制轴突再生的内在神经元机制，重点是表观基因组学 问题研究我们将阐明神经元索马周围的微环境对轴突的贡献 再生过程中，包括卫星神经胶质细胞和其他非神经元细胞。以确定是否有调查结果 在小鼠模型系统中预测人类生理学，我们将确定 感觉神经元周围的人类细胞。最后，我们建议操纵我们发现的新途径， 在两种中枢神经系统模型，脊髓损伤和视神经损伤中改善再生。该提案将使用 强大的工具组合，以追求创新的研究路线，旨在解剖多细胞 协调轴突再生的机制，并建立在这些发现的基础上，以改善中枢神经系统的再生 模型