Multicellular Mechanisms Driving Axon Regeneration

驱动轴突再生的多细胞机制

基本信息

批准号：
10624855
负责人：
Valeria Cavalli
金额：
$ 90.02万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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.

抽象的中枢神经系统（CNS）损伤后的永久性残疾是由于受伤者的失败而导致的轴突重建功能连接。目前没有任何疗法可以恢复活动能力和感觉脊髓损伤后或视神经损伤后视力。内在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原因，并且仍然是一个主要问题神经生物学。相反，周围感觉神经元在轴突后成功切换到再生状态受伤。我的研究计划的长期目标是了解多细胞机制受伤的感觉神经元激活促再生程序并确定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。由于基于个体基因的方法在轴突再生方面取得的成功有限，我们重点关注影响全球的表观基因组调控，特别是多个基因的组合。我们的目标是揭示表观遗传景观如何在轴突损伤的情况下重新组织，以使轴突维修。这些研究将结合细胞类型特异性表观基因组分析来研究转录和外周和中央轴突损伤引起的染色质构象变化。轴突再生不是细胞自主性，并在轴突损伤部位水平和细胞水平上受到环境的影响索玛。我们最近发现卫星胶质细胞是感觉神经节中胶质细胞的主要类型对轴突损伤做出反应并有助于修复过程。我们建议使用强大的工具组合追求创新的研究方向，旨在剖析编排轴突的多细胞机制再生并以这些发现为基础来改善中枢神经系统模型的再生。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，重点关注表观基因组学研究。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包括卫星胶质细胞和其他非神经元细胞。确定调查结果是否成立在小鼠模型系统中可以预测人类生理学，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改善两种中枢神经系统模型（脊髓损伤和视神经损伤）的再生。本提案将使用强大的工具组合，以追求旨在剖析多细胞的创新研究路线协调轴突再生的机制并基于这些发现来改善中枢神经系统的再生模型。