CNS Inflammation in Nervous and Mental Disease

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EXCEED THE SPACE PROVIDED. The chemokines monocyte chemoattractant protein (MCP-1) and macrophage inflammatory protein-1 alpha (MlP-la) are regularly observed in the brain during episodes of inflammation, and thus, are thought to be critical effectors in directing leukocyte infiltration into the central nervous system (CNS). Nevertheless, no direct evidence exists that either one of these two chemokines can actually stimulate leukocyte migration through the highly-impermeable blood-brain barrier (BBB). Moreover, it is completely unclear how these chemokines. which derive mainly from perivascular glia and extravasated leukocytes, exert their actions across the BBB. In light of the profound impact these substances could have on the course and treatment of neuroinflammatory disease, it is crucial that these issues be resolved. Toward this end, experiments are proposed to test the following hypothesis: Chemokines MCP-1 and MIP1- a stimulate mononuclear migration across the BBB, and do so by specific interactions with brain microvascular endothelial cells. Specifically, experiments will be aimed at clarifying the following issues: 1) Does MCP-1 or MIPl-cc, alone, have the capacity to stimulate transendothelial migration across the BBB. or does each need to work in concert with other proinflammatory cytokines? 2) By what mechanisms(s) might these chemokinesrelay their signals across the BBB? Initial experiments will use an in vitro model of the human BBB. developed in this laboratory, to directly measure the effects of MCP-1 and MlP-la on monocyte transendothelial migration. The next series of studies will utilize both this model and isolated human brain microvessels to investigate whether these chemokines are transported paracellularly or transcellularly across the specialized brain microvascular endothelium. Subsequent investigations will determine whether recognized receptors for these chemokines exist on the abluminal microvascular surface, and,if so, to examine their role in chemokine transport. The final experiments will illuminate microvascular responses to chemokine stimulation, e.g..altered adhesion molecule expression and permeability, which could support leukocyte infiltration. This study will be the first to characterize the interactions of MCP-1 and MlP-la at the BBB. Furthermore, in appreciation of the critical role of MCP-1 and MlP-la in CNS inflammation, these experimentswill greatly aid in comprehending pathogenetic mechanisms involved in this condition, and in developing novel therapeutics to antagonize chemokine actions in neuroinflammatorydisease. PERFORMANCE SITE ========================================Section End===========================================