Functional Diversity of Reactive Astrocytes in Spinal Cord Repair

项目概要/摘要 反应性星形胶质细胞作为中枢神经系统损伤后损伤结局的关键调节剂，是一个合理的细胞靶点 用于神经修复中枢神经系统损伤导致原发性病变处瘢痕形成星形胶质细胞增生， 远端轴突变性的区域，后者的特征很差。如果没有一个完整的理解 反应性星形胶质细胞亚型如何影响CNS损伤反应，利用 反应性星形胶质细胞就不太可能了长期目标是将知识的各种功能， 反应性星形胶质细胞来治疗CNS创伤。为实现这一目标，本提案的目的是确定 决定瘢痕形成和扩散的位置特异性功能的分子和细胞机制 受损脊髓的星形胶质细胞增生这一假说是瘢痕形成星形胶质细胞增生支持病理性的 巨噬细胞滞留在病变处的慢性瘢痕内，而弥漫性星形胶质细胞增生诱导轴突生长 脊髓损伤（SCI）后病变远端。这一建议的基本原理是，定义细胞内在 以及环境对反应性星形胶质细胞的多种功能的贡献将为如何靶向 反应性星形胶质细胞有效地用于CNS修复。基于强有力的支持数据，将对这一假设进行检验 通过追求三个具体目标：1）确定瘢痕形成星形胶质细胞在巨噬细胞维持中的作用， 慢性SCI瘢痕; 2）检查弥漫性星形胶质细胞增生在促进病变远端轴突生长中的作用;以及 3)评估通过AAV介导的方法局部改变瘢痕形成或弥漫性星形胶质细胞增生的效果 关于SCI康复这些研究将大大促进对反应性星形胶质细胞的理解， 开发新的星形胶质细胞靶向治疗方法，以减轻慢性瘢痕形成并促进轴突生长 SCI之后

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.