Functional Diversity of Reactive Astrocytes in Spinal Cord Repair

反应性星形胶质细胞在脊髓修复中的功能多样性

• 批准号: 10179595
• 负责人: Meifan Chen
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10179595
• 关键词: Area; Astrocytes; Attenuated; Axon; CSF1 gene; Cells; Chest; Chronic; Cicatrix; Corticospinal Tracts; Data; Diffuse; Distal; Functional disorder; Genetic; Glial Fibrillary Acidic Protein; Goals; Hindlimb; Human; Injury; Knock-out; Knowledge; Lateral; Lesion; Leucine Zippers; Location; Macrophage Colony-Stimulating Factor; Maintenance; Mediating; Microglia; Microinjections; Modeling; Molecular; Motor; Mus; Outcome; Paralysed; Pathologic; Pathway interactions; Phenotype; Phosphotransferases; Primary Lesion; Recovery; Regulation; Research; Role; Sensory; Site; Spinal; Spinal Cord; Spinal cord injury; Tamoxifen; Testing; Therapeutic; Tissues; Translating; Traumatic CNS injury; United States; Work; astrogliosis; axon growth; axonal degeneration; axonal sprouting; base; cellular targeting; central nervous system injury; disability; genetic manipulation; in vivo; injury and repair; injury recovery; insight; macrophage; monocyte; novel; overexpression; promoter; relating to nervous system; repair strategy; repaired; response to injury; restoration; spinal cord repair; targeted treatment; tool; translational approach

PROJECT SUMMARY / ABSTRACT As key modifiers of injury outcome following CNS insults, reactive astrocytes represent a rational cellular target for neural repair. CNS injury results in scar-forming astrogliosis at the primary lesion and diffuse astrogliosis in areas of distal axon degeneration, the latter of which is poorly characterized. Without a complete understanding of how reactive astrocyte subtypes impact the CNS injury response, harnessing the full therapeutic potentials of reactive astrocytes will remain unlikely. The long-term goal is to translate knowledge of the diverse functions of reactive astrocytes to treat CNS trauma. Towards this goal, the objective of this proposal is to identify the molecular and cellular mechanisms that determine location-specific functions of scar-forming and diffuse astrogliosis in the injured spinal cord. The hypothesis is that scar-forming astrogliosis supports pathological macrophage retention within the chronic scar at the lesion, whereas diffuse astrogliosis induces axon growth distal to the lesion after spinal cord injury (SCI). The rationale for this proposal is that defining the cell-intrinsic and environmental contributions to the diverse functions of reactive astrocytes will inform on how to target reactive astrocytes efficaciously for CNS repair. Based on strong supporting data, this hypothesis will be tested by pursuing three specific aims: 1) determine the role of scar-forming astrocytes in macrophage maintenance at the chronic SCI scar; 2) examine the role of diffuse astrogliosis in promoting axon growth distal to the lesion; and 3) assess the effects of locally modifying either scar-forming or diffuse astrogliosis by an AAV-mediated approach on SCI recovery. These studies will significantly advance understanding of reactive astrocytes and the ability to develop novel astrocyte-targeted therapeutic approaches to attenuate chronic scarring and promote axon growth after SCI.

项目摘要 /摘要 作为中枢神经系统损伤后的关键损伤结果修饰符，反应性星形胶质细胞代表一个理性的细胞靶 用于神经修复。中枢神经系统损伤导致原发性病变的疤痕形成星形胶质细胞增多，并在弥漫 远端轴突变性的区域，后者的特征很差。没有完全的理解 反应性星形胶质细胞亚型如何影响CNS损伤反应，并利用全部治疗潜力 反应性星形胶质细胞不太可能。长期目标是翻译了解的知识 反应性星形胶质细胞治疗中枢神经系统创伤。为了实现这一目标，该提议的目的是确定 确定疤痕形成和扩散的位置特异性功能的分子和细胞机制 受伤的脊髓中的星形胶质病。假设是形成疤痕的星形胶质病支持病理 病变处的慢性疤痕内的巨噬细胞保留，而弥漫性星形胶质细胞增生会诱导轴突生长 脊髓损伤后病变远端（SCI）。该提议的理由是定义细胞中心 以及对反应性星形胶质细胞的各种功能的环境贡献将告知如何针对目标 反应性星形胶质细胞有效地修复中枢神经系统。基于强大的支持数据，将检验该假设 通过追求三个具体目标：1）确定形成疤痕星形胶质细胞在巨噬细胞维持中的作用 慢性科幻疤痕； 2）检查弥漫性星形胶质症在促进病变远端的轴突生长中的作用；和 3）评估通过AAV介导的方法在局部修改疤痕形成或弥漫性星形胶质细胞增多的影响 关于SCI恢复。这些研究将显着提高对反应性星形胶质细胞的理解和 开发新型的星形胶质细胞靶向治疗方法来减轻慢性疤痕并促进轴突生长 科幻之后。