MECHANISM OF ACTION OF TYPE BETA TRANSFORMING GROWTH FACTOR

该项目的目的是确定类型的作用机制 β转化生长因子（TGF）在体外细胞培养和 体内动物研究。 将特别强调 识别在控制中活动的切换机制， 细胞对TGF-β的双功能反应，或者换句话说， 确定特定的基因表达，这导致，在一个 一方面，通过TGF-β刺激细胞增殖，另一方面， 另一方面，通过TGF-β抑制增殖。 到目前为止，三 已经发现不同种类的分子会影响 细胞转化为TGF-β;这些包括1）其他多肽生长因子，例如 如TGF-α、表皮生长因子和血小板衍生生长因子; 2)类维生素A和其他低分子量效应物;和3）癌基因， 其多肽产物。 每一类物质都是已知的 来影响基因表达。 将用于评估TGF-β的工具 在这个项目中的功能将包括特定的生物测定，受体测定， 免疫测定和TGF-β信使RNA测定。 研究旨在 两个水平：在整个动物中和在培养的细胞系中。 具体 用于这些研究的系统包括1）实验模型 在新生小鼠中研究TGF-β对诱导 对损伤的肉芽化型反应; 2）TGF-β对基质的影响 特定细胞类型的蛋白质被认为有助于观察到的 体内纤维化作用;和3）TGF-β调节的研究 将各种癌基因转染到细胞系中所带来的效应 对TGF-β有反应。

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.