Inflammatory pathways within the vasculature and at the blood brain barrier regulate the response of the vessel wall to injury. The unifying theme of this competitive program project renewal is that lipoprotein receptors (LRP1, LRP1B, and VLDLR) and the leukocyte and endothelial receptors integrin Mac-1 and VEcadherin modulate the inflammatory response in a cooperative fashion that is influenced by their ligands, tPA, PA1-1, and fibrin(ogen). The overall objective is to define molecular pathways by which LRP, Mac-1, tPA, PAI-1, and fibrin cooperate to modulate the inflammatory response during atherogenesis by regulating inflammatory cell migration and function to define mechanisms by which these molecules modulate the integrity of the blood brain barrier (BBB). These objectives will be achieved through the combined efforts of four principal investigators and three core facilities. Dr. Strickland (Project 1) will focus his research on the role of lipoprotein receptors in inflammation in the vessel wall. In collaboration with Dr. Zhang (Project 3) and Dr. Medved (Project 4), he will test the hypothesis that lipoprotein receptors, particularly LRP, regulate inflammatory processes by modulating the functional properties of integrins and their ability to interact with fibrin(ogen), thereby affecting macrophage migration. Using macrophage-specific LRP knockout mice, he will test the hypothesis that LRP participates in a novel signaling pathway that stimulates the production of pro-inflammatory cytokines. Dr. Lawrence (project 2) will investigate how association of tissue-type plasminogen activator with LRP modulates the integrity of the blood brain barrier in stroke, and the role of the integrin Mac-1 and fibrin in this response. Studies will test the hypothesis that targeting these interactions will lead to the development of more effective therapies for the treatment of ischemic stroke. Dr. Zhang (project 3) will investigated in role of tPA, LRP, PAI-1, Mac-1, and fibrin in macrophage efflux and test the hypothesis that LRP modulates this process by mediating integrin detachment and recycling. Dr. Medved (project 4) will investiage the role of fibrin(ogen) in the transendothelial migration of leukocytes, and along with Dr. Zhang will define the role of fibrin the inflammatory response. The three cores will be used by all projects to provide administratvie assistance (Core A), histology, microscopy and imaging assistance (Core B), and assistance in protein folding, proteomics and gene expression analysis (Core C).
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