This proposal entitled "Chemokine receptor function in the nervous system" seeks to determine the fundamental roles of chemokine signaling in the brain. During the previous funding period we determined that neural stem cells in the developing and adult nervous systems expressed chemokine receptors and that chemokines were important in regulating the directed migration and development of these cells. Thus, in CXCR4 chemokine receptor knockout mice structures in the nervous system such as the dentate gyrus (central nervous system) or dorsal root ganglia (peripheral nervous system) failed to develop properly. In addition, we demonstrated that chemokine receptors such as CXCR4 and CCR2 are expressed by neural stem cells in neurogenic regions of the adult brain including the dentate gyrus (DG) and the subventricular zone (SVZ). Furthermore, we demonstrated that in the adult DG SDF-1 was expressed and stored in neurons and cooperated with GABA in mediating early synaptic transmission to developing neural progenitors. In the present proposal we shall investigate whether these phenomena also apply to the development of adult neural progenitor cells involved in the repair response to brain damage. When the brain is damaged an innate immune response is activated. This involves the production of cytokines and chemokines by cells such as astrocytes and microglia. How do these molecules influence the brain's repair response? In response to ischemic stroke neural progenitors that express doublecortin migrate from the SVZ to new neurovascular stem cell niches in the stroke border zone. If they survive they may develop into new neurons that integrate into brain circuitry and contribute to repair. We shall study the role of chemokine signaling in the migration and development of new neurons in the stroke border zone. We shall use DCX-EGFP expressing mice to track the migration of new neurons to the stroke border zone and their juxtaposition to blood vessels and activated microglia and astrocytes. Electrophysiology will be used to investigate the synaptic inputs and excitability of developing neurons. In particular, we shall investigate whether these cells are responsive to key chemokines such as SDF-1 and MCP-1 whose expression is upregulated as part of the innate immune response. Finally, using a mouse genetic approach, we shall selectively delete the expression of key chemokines and their receptors from specific classes of cells and examine how this effect the neurogenic response to stroke and the effectiveness of brain repair. Overall, these studies will help to test our hypothesis that chemokine production helps to coordinate the brain's innate immune and repair responses and suggest novel therapeutic approaches for improving the efficiency of recovery from brain damage.
This research will investigate how activation of the immune system influences the nervous system's response to brain damage. Understanding this interaction will help to encourage more efficient brain repair and recovery in the face of neurodegenerative and demyelinating diseases. !
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