Multicellular Mechanisms Driving Axon Regeneration

摘要 中枢神经系统(CNS)损伤后的永久性残疾是由受伤的人失败造成的 轴突来重建功能连接。目前还没有恢复活动和感觉的疗法 脊髓损伤后或视神经损伤后视力。汽车固有的再生能力较差 成熟的中枢神经系统神经元是再生失败的主要贡献者，并且仍然是 神经生物学。相反，外周感觉神经元在轴突后成功地转换到再生状态 受伤。我的研究计划的长期目标是了解多细胞机制 受损感觉神经元激活促再生程序并确定未来治疗的潜在靶点 中枢神经系统损伤。 轴突生长计划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的成功有限，我们 专注于表观基因组调控，它影响全球，但特别是多个基因的组合。我们的 目的是揭示在轴突损伤的背景下，表观遗传景观是如何重新组织的，以使轴突 修理。这些研究将结合细胞类型的特定表观基因组分析来研究转录和 外周和中枢轴突损伤引起的染色质构象变化。轴突再生不是细胞 自主性，在轴突损伤部位和细胞水平上受环境影响 索玛。我们最近发现，感觉神经节中的主要神经胶质细胞--卫星胶质细胞 对轴突损伤做出反应，促进修复过程。我们建议使用强大的工具组合 追求一条创新的研究路线，旨在剖析轴突的多细胞机制 并在这些发现的基础上改进中枢神经系统模型的再生。为了实现这一目标，我们 将决定控制轴突再生的内在神经元机制，重点是表观基因组学 学习。我们将阐明神经元胞体周围的微环境对轴突的贡献。 再生过程中，包括卫星胶质细胞和其他非神经细胞。以确定调查结果是否 在小鼠模型系统中预测人类生理学，我们将确定分子图谱 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来 促进脊髓损伤和视神经损伤两种中枢神经系统模型的再生。这项提案将使用 强大的工具组合，以追求旨在解剖多细胞的创新研究路线 协调轴突再生的机制并在这些发现的基础上改进中枢神经系统的再生 模特们。

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.