The elastic properties of many vital tissues of the vertebrate body, including arteries, the lung and dermis, are due to the protein elastin, which is found in elastic extracellular matrix fibers. At present, there is only partial information concerning the regulation of elastin gene expression and the mechanisms involved in elastin fiber formation. In order to expand our understanding in these areas, a concerted, specific effort will be made to: 1) delineate the functional characteristics of the cis and trans-acting elements which modulate transcription of the elastin gene, 2) delineate mechanisms by which TNF-alpha and IL-1beta suppress transcription of the elastin gene, 3) utilize transgenic mice to study factors controlling expression of elastin in vivo, 4)delineate mechanisms of crosslink formation, and 5) define regions of the tropoelastin molecule which are important in fiber formation. To achieve these aims, the studies will employ a wide variety of modern molecular biologic (analysis of elastin promoter structure/function relationships by analysis of transfection of cultured cells and transgenic mice, recombinant expression of mutated forms of tropoelastin), and biochemical and cell biologic (immunochemical analysis of in vitro fiber assembly) methods, all of which are ongoing in the investigators' laboratory. Derangement of these elastic fibers either through heritable or acquired disease leads to a loss of elastic recoil, impairment of tissue function and in some cases death. Although the pathogenic mechanisms involved in this loss of elasticity have been delineated in broad outline in some disease entities, in the majority of cases they remain obscure. Definition of the molecular structure of these fibers and the mechanisms involved in their synthesis and assembly are requisite to understanding these derangements and to devising cures.
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