This is a competing continuation request for another five years of research support. The major focus of the proposed studies is upon the structure, function and properties of macromolecules of the extracellular matrix, examining the gene structure for the subunits of an unusual collagen and the molecular architecture and tissue distribution of a major chondroitin sulfate proteoglycan of skeletal muscle. The cuticle collagen of the invertebrate sandworm, Nereis virens, is a very unusual protein which has a molecular length of about 2400 nM and contains two dissimilar subunits. the chondroitin sulfate proteoglycan of skeletal muscle falls into the category of """"""""small"""""""" proteoglycans and it may participate in the recently described biological roles of proteoglycans in nerve regeneration and in clustering of acetylcholine receptors. In the case of the cuticle collagen, the objective is to discern the DNA structure of the genes which encode for the two subunits of this large protein. The cuticle collagen is about eight times larger than most collagen molecules and contains some unusual post-translational features including an extraordinarily high hydroxyproline content and a unique disaccharide, mannosyl- uronic acid. In the case of the chondroitin sulfate proteoglycan of skeletal muscle, the objectives are to characterize the molecular architecture of this complex glycoconjugate, to raise specific antibodies against it, and to use those antibodies to determine the distribution of the proteoglycan in the muscle. In addition, the antibodies will be used to potentially interfere with nerve regeneration and with neuromuscular transmission. These two projects encompass the scientific disciplines of biochemistry and molecular biology, utilizing contemporary methods to discern macromolecular structure and function as well as gene structure. The health-relatedness of the research applies to the general area of acquired and hereditary connective tissue diseases.
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