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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL030061-10
Application #
3341113
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1990-06-01
Project End
1993-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
10
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Rich, C B; Goud, H D; Bashir, M et al. (1993) Developmental regulation of aortic elastin gene expression involves disruption of an IGF-I sensitive repressor complex. Biochem Biophys Res Commun 196:1316-22
Horrigan, S K; Rich, C B; Streeten, B W et al. (1992) Characterization of an associated microfibril protein through recombinant DNA techniques. J Biol Chem 267:10087-95
Rich, C B; Ewton, D Z; Martin, B M et al. (1992) IGF-I regulation of elastogenesis: comparison of aortic and lung cells. Am J Physiol 263:L276-82
Wu, Y; Rich, C B; Lincecum, J et al. (1992) Characterization and developmental expression of chick aortic lysyl oxidase. J Biol Chem 267:24199-206
Jackson, L E; Faris, B; Martin, B M et al. (1991) The effect of beta-aminopropionitrile on elastin gene expression in smooth muscle cell cultures. Biochem Biophys Res Commun 179:939-44
Foster, J A; Rich, C B; Miller, M F (1990) Pulmonary fibroblasts: an in vitro model of emphysema. Regulation of elastin gene expression. J Biol Chem 265:15544-9
Foster, J A; Curtiss, S W (1990) The regulation of lung elastin synthesis. Am J Physiol 259:L13-23
Foster, J A; Rich, C B; Miller, M et al. (1990) Effect of age and IGF-I administration on elastin gene expression in rat aorta. J Gerontol 45:B113-8
Pollock, J; Baule, V J; Rich, C B et al. (1990) Chick tropoelastin isoforms. From the gene to the extracellular matrix. J Biol Chem 265:3697-702

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