GENOTOXIC MODULATION--HUMAN LIVER CELL DIFFERENTIATION

描述：（适用于研究者摘要）主要 拟议研究的目的是表征和理解 分子、细胞和生物化学事件， 人类上皮细胞的遗传毒性剂。人们认为 某些DNA碱基修饰的持续存在改变了基因表达， 可以改变细胞分化的阶段，并直接有助于 转变的状态。这项研究的假设是， 正常细胞的分化状态的变化，其可以是 转化表型的前体。因此，DNA损伤和 修复参与细胞免疫调节的选定基因 将在人肝上皮细胞中解决分化。这些 肝细胞培养物易于传代，具有复制活性， 许多体内器官的“特异性生化和分化 功能协调发展的这些可以提供与正常人肝脏相关的数据， 其他人类上皮组织。该项目目前的重点将是 来表征特定的致癌物DNA加合物的变化 在甲胎蛋白（FP）_、γ-谷氨酰转肽酶 (GFT)葡萄糖-6-磷酸酶（G6 P）和细胞角蛋白在这些细胞中， 转变。这些基因与活的特异性 细胞功能和分化，以及这些蛋白质的变化 发生在化学诱导肝癌的初始阶段。它 希望拟议的研究将提供新的信息， 深入了解导致人类细胞遗传毒性的机制。

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.