This program project application represents the combined efforts of a cohesive yet multidisciplinary group of investigators to delineate the role of fibronectin in processes directly relevant to the pathophysiological sequelae to injury and sepsis. Both basic and clinical studies have supported the concept that fibronectin serves an important role in these responses.
The aims will be achieved through the coordinated efforts of a Core and five scientific projects. The overall objectives of the five scientific projects are 1) To define and characterize the role of fibronectin and fibronectin receptors in binding and degradation of fibrin by mononuclear phagocytes. These studies will characterize these processes via mechanistic approaches in vitro and within experimental septic and thrombotic states in vivo. 2) To establish the role of adhesive glycoproteins and cellular receptors in supporting the interaction of platelets and leukocytes. The role of such binding in platelet-induced modification of leukocyte functions will also be addressed. 3) To assess the entrance of products of tissue injury into the vascular compartment and the role of fibronectin and fibronectin receptors in their vascular clearance and degradation. Studies will focus upon collagen and actin and will be completed in vivo in the context of burn injury and in vitro with isolated hepatic cells. 4) To assess the influence of the adherence of mononuclear phagocytes to endothelial derived matrix and individual matrix proteins on the functional activity of monocytes and inflammatory macrophages. Emphasis in these in vitro studies will be placed upon autocrine control of mononuclear phagocyte function via metabolites of arachidonic acid and monokines. 5) Evaluation of the mechanism by which fibronectin is incorporated into the subendothelial matrix. This study will examine the hypothesis that this process is subserved by regulation of the rate of fibronectin synthesis and polarization of fibronectin secretion and fibronectin receptors to the basal surface. The scientific sections will be supported by a Core which has responsibility for program administration, preparation of mononuclear phagocytes, preparative biochemistry, morphology, immunocytochemistry, and provision of statistical services. This overall effort will provide important basic information on the role of fibronectin and mononuclear phagocytes which may ultimately enhance the understanding of and therapeutic approaches to the injured patient.
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