The objectives of the proposed investigation are to determine the structural organization of the extracellular matrix and to establish the nature and mode of interactions between cells and the extracellular matrix and its specific components. These studies will focus on the structure and functions of heparan sulfate proteoglycans, which are found associated with the surface of adherent cells and in basement membranes and related matrix structures. The structural relationship between a membrane intercalated and a secreted proteoglycan will be determined. The structure of these proteoglycans which are synthesized in rat liver will be compared to that of a high molecular weight proteoglycan produced by basement membrane forming cells. Conventional biochemical methods and immunological techniques will be employed in these studies. The mechanisms responsible for the deposition of heparan sulfate proteoglycan in extra cellular matrix will be analyzed. Model systems consisting of fibroblasts and PYS cells in culture will be investigated. The hypothesis that heparan sulfate proteoglycans through interactions with other matrix components (i.e. fibronectin) may govern the assembly of an extra cellular matrix will receive special attention. The interaction between fibronectin and heparan sulfate proteoglycans will be studied in detail in test tube experiments and components that interfere with this interaction (i.e. fibronectin fragments and monoclonal antibodies) will be identified. These components will subsequently be used as tools to interfere with the assembly of extracellular matrix in cell culture systems. It is anticipated that results obtained in this investigation will yield important information concerning the functions of heparan sulfate in the normal physiology of cells and in the course of cancer, rheumatic and cardiovascular diseases including diabetic vascular complications.
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