BIOLOGY AND MOLECULAR BIOLOGY OF TRANSFORMING GROWTH FACTOR-BETA

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The purpose of the project is twofold: to study the biology of transforming growth factor-beta (TGF-beta), particularly in terms of its effects on cell function, and to investigate the molecular biology of TGF-beta with emphasis on both identifying possible additional members of the TGF-beta family and evaluating the degree of conservation between species of both the precursor and processed TGF-beta peptides. With respect to the biology of TGF-beta, one of the principal effects of the peptide on cells of mesenchymal origin is to control synthesis of matrix proteins. Thus, aberrant expression of TGF-beta might be expected to contribute to the excessive fibrosis characteristic of several disease processes. Indeed, it has been possible to correlate levels of TGF-beta in vitreous-aspirates of human eyes with the degree of severity of a fibrotic disease, proliferative vitreoretinopathy. Other lines of investigation have shown that the known ability of TGF-beta to regulate cellular proliferation and cellular differentiation might be important in the establishment of the-germ layers of developing amphibian embryo. Use of specific antibodies to TGF-beta, as well as assays to detect and quantitate the peptide, suggest that TGF- beta might be essential in induction of mesoderm from ectoderm. These interests in embryology have also resulted in the cloning and sequencing of three new genes for proteins related to TGF-betas in cDNA libraries of chicken and frog embryos, as well as in identification of mechanisms of control of TGF-beta expression such as alternate splicing of mRNAs and specific positive and negative regulatory control regions of the TGF-beta 1 promoter. Understanding the mechanisms which control TGF-beta expression will be important not only to developmental processes, but to disease processes as well.