Multicellular Mechanisms Driving Axon Regeneration

驱动轴突再生的多细胞机制

• 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
• 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/10624855
• 关键词: Affect; Afferent Neurons; Automobile Driving; Axon; Biological Models; Cells; Central Nervous System; Chromatin; Environment; Epigenetic Process; Esthesia; Failure; Future; Genes; Genetic Transcription; Goals; Human; Individual; Lead; Molecular Conformation; Molecular Profiling; Mus; Natural regeneration; Nervous System Trauma; 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; 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.

抽象的 中枢神经系统（CNS）受伤失败造成的永久残疾 轴突重建功能连接。目前尚无恢复移动性和感觉的疗法 脊髓损伤或视力损伤后。内在再生能力不佳 成熟的CNS神经元是再生失败的主要因素，并且仍然是一个主要问题 神经生物学。相反，周围感觉神经元成功切换到轴突后的再生状态 受伤。我的研究计划的长期目标是了解多细胞机制 受伤的感官神经元激活了促增长程序，并确定未来治疗的潜在目标 中枢神经系统受伤。 轴突生长程序的激活部分取决于再生相关基因的表达。 因为基于基因的方法在轴突再生方面取得了有限的成功，所以我们是 专注于表观基因组法规，这些法规影响了全球，但尤其是多个基因的组合。我们的 目标是发现如何在轴突损伤的背景下重新组织表观遗传景观以实现轴突 维修。这些研究将结合细胞类型的特定表观基因组学分析，以研究转录和 外围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，受轴突损伤部位和细胞水平的环境的影响 索马。我们最近发现，卫星神经胶质细胞是感觉神经节中神经胶质细胞的主要类型 应对轴突损伤并为维修过程做出贡献。我们建议使用强大的工具组合 追求旨在解剖多细胞机制的创新研究线 再生和基于这些发现以改善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固有神经元机制，重点是表观基因组学 研究。我们将阐明神经元周围微环境对轴突的贡献 再生过程，包括卫星神经胶质细胞和其他非神经元细胞。确定是否提出 在小鼠模型系统中是人类生理学的预测，我们将确定 感官神经元周围的人类细胞。最后，我们建议操纵我们发现的新颖途径 改善两种CNS模型的再生，脊髓损伤和视神经损伤。该建议将使用 旨在剖析多细胞的创新研究系列工具的强大组合 策划轴突再生并建立这些发现以改善CNS再生的机制 型号。

项目成果

Hyperexcitability of Sensory Neurons in Fragile X Mouse Model.

• DOI: 10.3389/fnmol.2021.796053
• 发表时间: 2021
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Deng PY;Avraham O;Cavalli V;Klyachko VA
• 通讯作者: Klyachko VA

Analysis of neuronal injury transcriptional response identifies CTCF and YY1 as co-operating factors regulating axon regeneration.

• DOI: 10.3389/fnmol.2022.967472
• 发表时间: 2022
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Avraham, Oshri;Le, Jimmy;Leahy, Kathleen;Li, Tiandao;Zhao, Guoyan;Cavalli, Valeria
• 通讯作者: Cavalli, Valeria

Genome-wide chromatin accessibility analyses provide a map for enhancing optic nerve regeneration.

• DOI: 10.1038/s41598-021-94341-y
• 发表时间: 2021-07-21
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Pita-Thomas W;Gonçalves TM;Kumar A;Zhao G;Cavalli V
• 通讯作者: Cavalli V

Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model.

• DOI: 10.3389/fnmol.2021.796070
• 发表时间: 2021
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Avraham O;Deng PY;Maschi D;Klyachko VA;Cavalli V
• 通讯作者: Cavalli V