Wound healing is a dynamic process involving multiple coordinated events, including recruitment of leukocytes to the injury site, removal of the provisional matrix and cell debris, production of cytokines and growth factors, cell and matrix regeneration, etc. A number of in vitro and in vivo studies have provided strong evidence for the involvement of leukocytes, the fibrinolytic system (Plg, uPA, uPAR and Fg), have alphabbeta2 integrin, and the endocytic pathways (e.g. LRP) in wound healing is currently unknown. Given the paramount importance of wound healing and the fact that dysfunction of wound healing contributes to many chronic diseases such as atherosclerosis associated with myocardial infarction and stroke, restonosis after angioplasty, and rheumatoid arthritis, the long term goal of this laboratory is to understand the molecular mechanisms underlying the wound healing process. Toward this goal, we have initially focused on the interactions of ampha4beta2 with Fg and uPAR, and identified partial sequences that mediate these interactions. Since many cell types produce both uPA and PAI-1 in response to injury, and the PAI-1-uPA complex, and thereby participate in wound healing by modulating alpha2beta2-mediated monocyte cell migration and fibrin degradation. We will test this hypothesis by identifying the binding interface between alpha2beta2 and uPAR, using our established homolog-scanning mutagenesis approach, and study the mechanisms by which uPAR and LRP modulate the functions of alphambeta2. The importance of the alpha4beta2/uPAR/LRP system in vivo wound healing will be tested by reconstituting this system in alphambeta2- and uPAR-deficient mice, as well as monocyte specific LRP-deficient mice, using bone marrow transplant technology and transgenic technology. Overall, these studies will provide insight into the mechanisms and functional consequences of the alphaMbeta2/uPAR/LRP interactions in wound healing. Such information will not only help us understand the physiology of the fundamental process, it may also assist in the development of new strategies and therapeutic interventions that will block the pathogenesis of many diseases, such as myocardial infarction, stroke, and rheumatoid arthritis, as well as tumor growth.
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