GENOTOXIC MODULATION--HUMAN LIVER CELL DIFFERENTIATION

描述：(改编为调查人员摘要)主要 拟议研究的目标是描述和理解 暴露后发生的分子、细胞和生化事件 人类上皮细胞对遗传毒性物质的敏感性。据认为， 某些DNA碱基修饰的持久性改变了基因的表达 可能改变细胞分化的阶段，并直接导致 转变后的状态。这项研究的假设是，遗传毒素导致 正常细胞分化状态的改变，这可能是 转化表型的前驱。因此，DNA损伤和 参与细胞调控的选定基因的修复 将解决人肝上皮细胞的分化问题。这些 肝细胞培养很容易传代，复制活跃，并表现出 体内器官的许多“特异的生化和分化” 功能。这些数据可以提供与正常人体肝脏和 其他人类上皮组织。该项目目前的重点将是 表征与变化相关的特定致癌物DNA加合物 甲胎蛋白(FP)基因中的γ-谷氨酰转肽酶 这些细胞的GFT、葡萄糖-6-磷酸酶(G6P)和细胞角蛋白 继续转型。这些基因与活体特异的 细胞功能和分化，以及这些蛋白质的变化 发生在化学诱导的肝癌的早期阶段。它 希望拟议的研究将提供新的信息和 对导致人类细胞遗传毒性的机制的洞察。

DESCRIPTION: (Adapted for the investigators's abstract) The primary objective of the proposed research is to characterized and understand the molecular, cellular and biochemical events that occur following exposure of human epithelial cells to genotoxic agents. It is thought that the persistence of certain DNA base modifications alter gene expression which may change the stage of cellular differentiation and directly contribute to the transformed state. The hypothesis of the study is that genotoxins cause a change in the differentiated state of the normal cell which may be a precursor to the transformed phenotype. Thus, the role of DNA damage and repair in the modulation of selected genes involved in cellular differentiation will be addressed in human liver epithelial cells. These liver cell cultures are easily subpassed, replicatively active and exhibit many of the in vivo organ "specific biochemical and differentiated functions. These can provide data relevant to the normal human liver and other human epithelial tissues. The present focus of this project will be to characterize the specific carcinogen DNA adducts associated with changes in the genes for alpha-fetoprotein (FP)_, gamma-glutamyl transpeptidase (GFT), glucose-6- phosphatase (G6P) and cytokeratins in these cells that go on to transformation. These genes are associated with live specific cellular function and differentiation, and alternations in these proteins occur during the initial stages of chemically induced hepatocarcinoma. It is hoped that the proposed studies will provide new information and insights into the mechanisms that lead to human cell genotoxicity.