ELASTIC FIBER STRUCTURE, FIBROGENESIS DISEASE

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Elastic fibers play an essential role in the structural integrity and function of large blood vessels. Their degradation has been implicated in the pathogenesis of clinically significant cardiovascular diseases. There are at least two major protein components of elastic fibers referred to as elastin and microfibril. The overall aims of this proposal are to define the mechanisms involved to the regulation of elastic fibers in development and repair states. Using chick aortic tissue and cells, the syntheses of tropoelastin and microfibril will be examined at transcriptional, translational and post-translational levels. The extracellular deposition of tropoelastin molecules to form insoluble elastin will be measured by quantitating desmosine and aldol condensation crosslinks. Antibodies and cDNAs specific for different tropoelastin isoforms and microfibril will be used to define differential synthesis and extracellular deposition. Both in ovo and in vitro (organ culture and smooth muscle cell cultures) studies are proposed using different aged embryos. In order to define hormonal regulation and response to any injury- induced situation, cell culture matrices will be subjected to limited digestion with elastase. The response of elastic fiber synthesis to this injury will be studied in the presence and the absence of hormones, isolated elastin peptides and synthetic tropoelastin peptides. Possible autocrine responses involving insulin-like growth factor I (IGF-I) and synergistic actions between glucocorticords and growth factors will be explored. In order to perform the necessary quantitations and extracellular immunoelectron microscopic localizations, specific oligonucleotide peptides and antibodies will be generated based on data obtained from nucleotide sequencing of tropoelastin and microfibril mRNAs. Use of automated DNA and peptide synthesizers will facilitate these studies.