This proposal by a group that has a long history of productive collaboration aims at providing a better understanding of cell extracellular matrix interactions at the molecular level. The program integrates the use of recombinant DNA, protein and peptide chemistry, immunochemistry and cell biology techniques for these studies. Work done within this program has identified the Arg-Gly-Asp (RGD) tripeptide as an important cell attachment signal that is responsible for the recognition of fibronectin and other adhesive proteins by cells. Tjhis led to the identification and subsequent cloning of receptors for several of the adhesion proteins. Moreover, proteoglycan core proteins and proteins carrying polylactosaminoglycan chains have been cloned and novel basement membrane components identified. The focus and the key personnel of the program will remain unchanged; the new initiatives relate to the progress of the projects and new technologies to be applied. The cell adhesion studies will focus increasingly on the family of receptors known as integrins. The important questions in this field relate to the nature of signals transmitted to cells through the ligation of these receptors, the regulation of receptor expression and the ligand specificity of the receptors. The first two questions will be approached with gene transfer studies and genomic cloning. Studies on the ligand specificity of the receptors will combine recombinant DNa approaches with a new direction in the program, analysis of the cell attachment sites of adhesion proteins by protein crystallography and peptide NMR. These studies are expected to yield new RGD adhesion peptides with improved affinities and restricted receptor specificities. Such peptides will be important, for example, for further analysis of the inhibitory activity that the RGD peptides have on tumor invasion. the proteoglycan studies will focus on two areas: the analysis of proteoglycan biosynthesis with mutated recombinant core proteins and the elucidation of proteoglycan functions by gene transfer. This latter approach has opened up an important new lead in that one of the cloned proteoglycans may turn out to be an inhibitor of cell proliferation. The basement membrane studies have led to the identification of a new basement membrane protein, merosin, which has a restricted tissue distribution. Future studies will aim at the elucidation of the functional significance of merosin.
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