Project 2: "Neuroprotective mechanisms of CXCL12 during CNS demyelinating diseases" The molecular mechanisms responsible for leukocyte migration and activation within the CNS parenchyma are unknown, as are the mechanisms that orchestrate recovery and myelin repair during remitting phases of both MS and EAE. Blood-brain barrier (BBB) disruption and demyelination are consequences of white matter inflammatory infiltrates22"25. Utilizing confocal microscopy, Dr. Robyn Klein observed the loss of endothelial cell expression of the chemokine CXCL12, normally displays basolateral localization, during CNS autoimmune disease, suggesting CXCL12 plays a role in regulating the blood-brain barrier (BBB). Dr. Klein's team also observed that spinal cord motorneurons express CXCL12 and white matter oligodendrocyte precursors express its receptor CXCR4, suggesting a role for these molecules in remyelination. Thus, a novel, antiinflammatory role for CXCL12 whereby it functions to localize CXCR4-expressing mononuclear cells to the perivascular space, thus limiting their parenchyma! infiltration and activation is proposed in Project 2. Thus, Project 2 will (1) determine how CXCL12-mediated perivascular localization regulates mononuclear cell trafficking during CNS autoimmunity, (2) determine how perivascular localization regulates mononuclear cell activation during CNS autoimmunity, and (3) evaluate how CXCL12 regulates the remyelination process.