Heparan sulfate proteoglycan is a protein polysaccharide conjugate found on surfaces and in extracellular matrices where it contributes to many of the normal functions of cells. The structure and expression of this molecule might be disrupted in such conditions as the rejection of transplants. The hypothesis is advanced that the metabolism of heparan sulfate proteolgycan in blood vessels, as it might occur in injury and inflammation (i) deprives blood vessels of normal functional properties such as the ability to prevent coagulation and to present a barrier to the egress of plasma proteins and blood cells; (ii) induces the maturation of cells that activate the immune in response to foreign cells and proteins and (iii) causes the cells that line blood vessels, endothelial cells, to adopt new functional properties which promote inflammation and coagulation. The goals of this project are three. First, enzymes in the blood and blood vessels that contribute to the degradation of heparan sulfate proteoglycan will be characterized and inhibitors of those enzymes developed. These studies will use insights gained by correlating the structural properties of the enzymes with the function. Second, the mechanisms by which the products of those enzymes act on the antigen presenting cells which trigger immune responses and blood vessels will be elucidated. These studies will utilize cultured endothelial cells and bone marrow cells as model systems. Third, novel therapeutic approaches will be tested for interfering with this system with the goal of delaying or preventing the rejection of transplants or limiting the amount of tissue damage associated with the rejection of transplants. These studies will use allo- and xenotransplant models.
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