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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044907-03
Application #
6982792
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Jacobs, Tom P
Project Start
2003-12-01
Project End
2007-03-31
Budget Start
2005-12-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$241,434
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Stamatovic, Svetlana M; Keep, Richard F; Andjelkovic, Anuska V (2011) Tracing the endocytosis of claudin-5 in brain endothelial cells. Methods Mol Biol 762:303-20
Hoffman, William H; Stamatovic, Svetlana M; Andjelkovic, Anuska V (2009) Inflammatory mediators and blood brain barrier disruption in fatal brain edema of diabetic ketoacidosis. Brain Res 1254:138-48
Stamatovic, Svetlana M; Keep, Richard F; Wang, Michael M et al. (2009) Caveolae-mediated internalization of occludin and claudin-5 during CCL2-induced tight junction remodeling in brain endothelial cells. J Biol Chem 284:19053-66
Dimitrijevic, Oliver B; Stamatovic, Svetlana M; Keep, Richard F et al. (2007) Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke 38:1345-53
Latash, Mark L; Scholz, John P; Schoner, Gregor (2007) Toward a new theory of motor synergies. Motor Control 11:276-308
Stamatovic, Svetlana M; Dimitrijevic, Oliver B; Keep, Richard F et al. (2006) Protein kinase Calpha-RhoA cross-talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem 281:8379-88
Stamatovic, S M; Dimitrijevic, O B; Keep, R F et al. (2006) Inflammation and brain edema: new insights into the role of chemokines and their receptors. Acta Neurochir Suppl 96:444-50
Stamatovic, Svetlana M; Keep, Richard F; Mostarica-Stojkovic, Marija et al. (2006) CCL2 regulates angiogenesis via activation of Ets-1 transcription factor. J Immunol 177:2651-61
Dimitrijevic, Oliver B; Stamatovic, Svetlana M; Keep, Richard F et al. (2006) Effects of the chemokine CCL2 on blood-brain barrier permeability during ischemia-reperfusion injury. J Cereb Blood Flow Metab 26:797-810
Stamatovic, Svetlana M; Shakui, Parvin; Keep, Richard F et al. (2005) Monocyte chemoattractant protein-1 regulation of blood-brain barrier permeability. J Cereb Blood Flow Metab 25:593-606