MECHANISM OF ACTION OF TYPE BETA TRANSFORMING GROWTH FACTOR

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The purpose of the project is to determine the mechanism of action of type beta transforming growth factor (TGF) both in cell culture in vitro and in animal studies in vivo. Particular emphasis will be placed on identification of the switching mechanisms active in control of the bifunctional responses of cells to TGF-beta, or, stated differently, on determination of the particular gene expression which leads, on the one hand, to stimulation of cell proliferation by TGF-beta, and, on the other hand, to inhibition of proliferation by TGF-beta. Thus far, three different classes of molecules have been found to influence the response of cells to TGF-beta; these include 1) other polypeptide growth factors such as TGF-alpha; epidermal growth factor, and platelet-derived growth factor; 2) retinoids and other low-molecular weight effectors; and 3) oncogenes and their polypeptide products. Each of these classes of substances is known to affect gene expression. Tools that will be used to assess TGF-beta function in this project will include specific bioassays, receptor assays, immunoassays, and assays for TGF-beta messenger RNA. Studies are aimed at two levels: in the whole animal and in cell lines in culture. Specific systems employed for these investigations include 1) an experimental model in the newborn mouse for studying the effects of TGF-beta on induction of a granulation-type response to injury; 2) effects of TGF-beta on matrix proteins of specific cell types thought to contribute to the observed fibrotic effects in vivo; and 3) study of the modulation of TGF-beta effects brought about by transfection of various oncogenes into cell lines responsive to TGF-beta.