The unifying theme of this competitive program project renewal application is to define the molecular mechanisms regulating inflammatory and angiogenic events that occur in the vessel wall. These objectives will be achieved through the combined effort of three principal investigators and three core directors. Dr. Strickland will focus on a novel signaling pathway in which ligand association with LRP leads to production of inflammatory cytokines and chemokines. The ligands responsible for initiating this response and the signaling pathways involved will be delineated. The role of components of the urokinase pathway and the integrin alphambeta2 in this response will be investigated in collaboration with Dr. Lawrence and Dr. Zhang, respectively. The significance of this pathway will be evaluated in macrophage tissue-specific LRP knockouts using a mouse model of atherosclerosis. Dr. Lawrence will focus on PAI-1 and its role in the control of vascular cell migration and angiogenesis. Mechanisms defining vascular cell migration and the role of PAI-I, vitronectin, uPA, and uPAR in this process will be examined in mice that are genetically deficient in these components. The role of LDL receptor family members (LRP and the VLDL receptor) in angiogenesis and vascular cell migration will also be examined in collaboration with Dr. Strickland (Project 1). Additionally, the importance of uPAR's association with integrins during vascular cell migration and angiogenesis will be examined in collaboration with Dr. Zhang. Dr. Zhang will investigate the role of the uPA/uPAR system in modulating wound healing events in the vessel wall that are mediated by the integrin, alphambeta2. The molecular mechanisms by which uPAR modulates alpha4beta2 function and their roles in wound healing in vivo will be explored in collaborative studies with Dr. Lawrence. In collaboration with Dr. Strickland, the mechanism by which LRP may regulate cell surface levels of uPAR and alphambeta2 will be explored. The three cores will be used by all projects to provide administrative assistance, pathology services and fluorescence microscopy, and examination of protein folding and quantification of protein-protein interactions.
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