The long-term objectives of these studies continue to be understanding the molecular basis of assembly of specific tissue and organ structures, i.e. morphogenesis. Work of the previous period of funding has demonstrated that tissue-dependent expression of transcript and protein variants of non-fibrilar collagens (types IX, XII, XIV, and XVIII) determines the microarchitecture of extracellular matrix in different tissues. For the next project period a combination of DNA cloning, immunohistochemistry, protein chemistry and crystallography, cell culture studies, and transgenic mice technology will be used to analyze the interaction properties, processing and function(s) of the nonfibrillar collagen XVIII, and the basis for the inhibitory effects on endothelial cell proliferation and tumor growth in mice associated with a proteolytic fragment, endostatin. Linkage mapping, candidate gene cloning, mutation detection and analyses of transgenic mice will provide the basis to further examine the role of a receptor tyrosine kinase signal transduction pathway in regulating the interaction between endothelial cells and their underlying extracellular matrix. These studies will contribute significantly to the understanding of normal tissue and organ morphogenesis and provide a basis for improved therapeutic strategies in disease processes of tissue repair, cancer and genetic abnormalities.
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