Chemokine Effects on Blood-brain Barrier Permeability

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): The increasing body of evidence implicates inflammation as a significant contributor to death and destruction of neuronal tissue that accompanies an episode of a cerebral ischemia. During the acute inflammatory response to ischemia/reperfusion (I/R) condition, highly destructive leukocytes are directed into the brain by an orchestrated interplay of molecular signals provided by diversity of cytokines, adhesive molecules and mainly chemokines. In particular, the chemokine monocyte chemoattractant protein-1 (MCP-1) is considered to be one of the main effectors driving postischemic infiltration into the brain parenchyma. Furthermore, secretion and existence of MCP-1 in the perivascular space of blood brain barrier (BBB) implicates their role not only in the composition of chemoattract gradient but also in the possible activation of endothelial cells and rearrangement of the junction complexes. In order to elucidate a novel possible function of MCP-1 during an inflammatory response, we propose a research plan directed at testing of the following hypothesis: MCP-1 induces rearrangement of brain endothelial cells junction complexes and thus contributes to alteration in the BBB permeability during inflammatory response and ischemial-reperfusion (I/R) injury. Specifically we will investigate effect of MCP-1 on brain endothelial permeability in vitro (purified culture of brain endothelial cells as well as co culture of astrocytes and endothelial cells) and in vivo (injection of MCP-1 into the brain parenchyma or intracerebroventricular). Also, we will estimate real effect of MCP-1 on BBB permeability during an inflammatory reaction using in vitro and in vivo model of ischemia reperfusion injure. Collectively, results from these studies will provide a foundation for developing novel therapeutic strategies to lessen the ravages of stroke as well as other inflammatory process in CNS.