The regulatory mechanisms that control the production of type I collagen pose a challenge to biologists interested in the regulation of gene expression and to clinicians concerned with connective tissue disorders. Type I collagen represents a major secreted product of fibroblasts, osteocytes, smooth muscle cells and a host of other mesenchymal cells. There is therefore no tissue whose structural integrity is not dependent on an appropriate balance between the synthesis and degradation of this matrix component. Since we know that collagens also function in cell- matrix interactions to instruct cellular activity during morphogenesis and in tissue repair, the need for careful regulation of matrix production becomes even more clearcut. The regulation of collagen synthesis can and probably does occur at many levels during the elaboration of this complex macromolecule. Nevertheless, there is increasing evidence that transcription and related steps that influence the level of functional mRNAs for the alpha1(I) and alpha2(I) chains of type I collagen serve as major control points. Fundamentally, transcriptional control is generated by the interaction of a complex set of cis-acting regulatory elements in DNA with a corresponding set of trans-acting DNA-binding proteins. The way in which this transcription complex functions is influenced by signals generated by interactions of cytokines with cellular receptors; in the case of collagen gene expression, TGF-beta, IL-1, IL-6 and gamma-interferon appear to play important roles. This project will concern itself with a thorough characterization of the transcription complexes that serve to regulate the rate of collagen gene transcription and to achieve coordinate control of the two genes. Regulatory elements in the promoters and first introns of the human alpha1(I) and alpha2(I) collagen genes will be defined and the way in which these elements interact via transcription factors will be elucidated. The manner in which cytokines influence the function of transcription complexes will be determined. In selected cases, novel transcription factors will be purified and characterized and their genes cloned. Factors that contribute to the stability of collagen mRNAs will be examined. The nature of mutations that transcriptionally inactivate type I collagen genes and lead to the genetic disorder, osteogenesis imperfecta type I, will be elucidated. If a thorough characterization of the processes that effect transcriptional control of type I collagen genes can be achieved, it is likely that therapeutic control of collagen production can be designed.
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