Functional Diversity of Reactive Astrocytes in Spinal Cord Repair

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.