Collagen is a major component of connective tissue. Its synthesis is altered in many disease processes, increasing in fibrotic conditions and abnormal scarring and decreasing in impaired wound healing. The proposed studies are aimed at understanding the molecular mechanisms responsible for: (1) Inhibition of collagen synthesis by benzoic hydrazide; and (2) inhibition of lysyl hydroxylase expression by minoxidil. Among the parameters that will be studied are type-specific collagen synthesis, procollagen mRNA stability, procollagen gene transcription and posttranslational modifying enzymes prolyl hydroxylase and lysyl hydroxylase. Transcriptional mechanisms will be explored with chimeric genes containing promoter sequences for collagen or lysyl hydroxylase genes linked to appropriate reporter genes. These genes will be inserted into fibroblasts to examine influences on promoter activity. The eventual goal of this research is to identify regulatory molecules and to define the nature of their interaction with genes enabling us to design additional effector molecules that can modulate gene expression. An understanding of the transcriptional effects of minoxidil or benzoic hydrazide may lead to effective strategies for controlling excessive collagen accumulation in fibrotic conditions.
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