- In three specific aims the applicant will study the biology and pathology of the elastic fiber system. In the first aim the applicant will investigate the regulation of the elastin gene expression in cultured cells and transgenic mice with emphasis on the role of cis elements and transacting factors critical for transcriptional regulation of the human elastin promoter. These studies will concentrate on TGF-beta and UV irradiation.
The second aim will explore the molecular interactions of the elastic fiber network proteins necessary for elastin fibrillogenesis. These studies will utilize the yeast two-hybrid system to identify proteins binding to elastin and big-h3, a microfibrillar protein, by utilizing constructs with cloned human cDNAs in the two-hybrid binding domain. The interacting clones will be characterized, and the physiological relevance of the interactions will be confirmed by immunoprecipitation and protein overly assays. These studies are expected to provide critical information of the molecular interactions necessary for proper assembly of the elastic fibers during development, growth, and repair. In the third aim the applicant will search for mutations that cause pseudoxanthoma elasticum (PXE), a multisystem heritable disorder affecting skin, eyes, and the cardiovascular system. They will concentrate on candidate genes in an approximately 500kb locus identified by an international consortium on chromosome 16p13.1. The applicant expects these approaches will allow specific defects in the genes involved in elastin fibrillogenesis to be described. Collectively the applicant expects the proposed studies will have major implications towards understanding the factors regulating the expression of the elastin gene, assembly of the elastic fibers in normal cells and tissues, and their alterations in diseases with aberrant elastic fibers.
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