PATHOLOGY OF CHEMICAL CARCINOGENISIS

化学致癌的病理学

• 批准号: 3165469
• 负责人: GARY A CLAWSON
• 金额: $ 18.03万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1987-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165469
• 关键词: RNA; RNA directed DNA polymerase; acetamides; azo compounds; chemical carcinogen; chemical carcinogenesis; chromatin; chromatography; disease /disorder model; electron microscopy; gel electrophoresis; gene expression; genetic transcription; heterogeneous nuclear RNA; liver cells; liver neoplasms; membrane permeability; neoplasm /cancer genetics; nitrosamines; nucleic acid metabolism; radiotracer; tissue /cell culture

The mechanisms underlying chemically-mediated malignant transformation are to be explored. Model systems to be used include in vivo exposure of rodents to thioacetamide, ethionine, alkylnitrosamines, and amino azo dyes. In vitro exposure of hepatocyte cultures to these same agents will also be employed. Previous data show a modification of nuclear restriction of RNA species in liver cells exposed to carcinogens, potentially representing an initiating or a promoting event, or both. The major areas to be investigated include: (1) an analysis of the cell-free model of nuclear RNA transport to determine the role of high-energy bond hydrolysis as a driving force, and to assay for the significance of both selection of RNA species for secretion and for back-diffusion to the nucleus; (2) an analysis of in vivo restriction in the two-stage model of hepatocarcinogenesis to learn whether "nuclear leakage" is related to initiation or to promotion; (3) the fidelity of the in vitro system will be surveyed. Specific cDNA probes for messenger species (Alpha1-glycoprotein and AlphaMu-globulin) will be used to measure messenger release in vivo and compare these data to in vitro release following turpentine and androgenic stimulation of male rats. Additionally, these cDNA probes will be used to isolate the messengers in vivo and in vitro to compare splicing, processing, and polyadenylation following the release in vivo and in vitro; 4) an attempt wil be made to purify and characterize the nuclear matrix and nuclear envelope NTase and to define their role in transport. The potential that these also represent an ATP driven endonuclease will be tested. This point seems relevant to the apparent frequency of genetic information relocation associated with oncogene expression. These experiments will be used to test the hypothesis that malignant transformation involves alterations in the transcription and processing of RNA, at least as a basis for the phenotypic expression of cancer.

化学介导的恶性转化的机制是 有待探索 使用的模型系统包括体内暴露 啮齿类动物对硫代乙酰胺、乙烯利、烷基亚硝胺和氨基偶氮 染料。 肝细胞培养物在体外暴露于这些相同的试剂， 也被雇用。 先前的数据显示， 暴露于致癌物的肝细胞中的RNA种类， 表示发起或促进事件或两者。 的主要领域 研究内容包括：（1）分析无细胞模型， 核内RNA运输的高能键水解作用决定 作为驱动力，并分析两种选择的意义， 用于分泌和反向扩散到细胞核的RNA种类;（2） 两阶段模型中的体内限制性分析 肝癌发生，以了解“核泄漏”是否与 启动或促进;（3）体外系统的保真度将是 调查过了 信使物质（α 1-糖蛋白）的特异性cDNA探针 和α μ-球蛋白）将用于测量体内信使释放， 将这些数据与经尿道前列腺切除术和雄激素治疗后的体外释放进行比较， 刺激雄性大鼠。 此外，这些cDNA探针将用于 在体内和体外分离信使以比较剪接， 处理，以及体内和体外释放后的聚腺苷酸化; 4)将尝试纯化和表征核基质， 核膜NTase，并确定其在运输中的作用。 的 这些也代表ATP驱动的核酸内切酶的可能性将是 测试. 这一点似乎与遗传的明显频率有关。 与癌基因表达相关的信息再定位。 这些 实验将被用来测试的假设，恶性 转化涉及转录和加工的改变， RNA，至少作为癌症表型表达的基础。