ASBESTOS AND NO2 IN ENVIRONMENTAL LUNG DISEASE

环境性肺病中的石棉和二氧化氮

• 批准号: 6382271
• 负责人: NICHOLAS H HEINTZ
• 金额: $ 28.64万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-15 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6382271
• 关键词: apoptosis; asbestos; autoradiography; biomarker; cell cycle; cell growth regulation; cell proliferation; cyclin dependent kinase; cytology; cytotoxicity; environmental toxicology; enzyme induction /repression; enzyme inhibitors; fibroblasts; flow cytometry; free radical oxygen; laboratory mouse; laboratory rat; lung injury; nitrogen oxides; nuclear factor kappa beta; occupational disease /disorder; respiratory epithelium; tissue /cell culture; transcription factor

DESCRIPTION Exposure of the human lung to environmental particulates and gases contributes to a variety of diseases, including pulmonary fibrosis and cancer. Previous work in our research group has shown that asbestos, reactive oxygen species (ROS), and reactive nitrogen species (RNS) trigger specific cell signaling pathways in target cells of the lung, leading to activation of transcription factors such as AP-1 and NF-KB. These and other transcription factors are involved in cellular decisions leading to phenotypic changes involved in the initiation of lung disease. To extend our understanding of cellular responses to mixtures of chemical and physical agents, we propose to study the effects of chrysotile asbestos and nitrogen dioxide (NO2), either alone or together, on three endpoints of exposure: cell survival, cell cycle progression, and apoptosis. First, we will characterize the responses of rat lung epithelial (RLE) cells and rat lung fibroblasts (RLF) to asbestos and/or N02, in regard to the activation of the transcription factors AP-1, NF-KB, and E2F and their downstream target genes. Activation of cyclin-dependent kinases (CDKs), metabolism of their protein inhibitors (i.e., CKIs p15, pl6, pl8, p2l, and p27),and phosphorylation of retinoblastoma family proteins (pRB and pl3O) will be studied as regulators of cell cycle progression. Cell imaging techniques, flow cytometry and activation of proteases will be used to measure apoptotic responses. Transient expression of dominantnegative regulatory molecules will be used to dissect mechanisms of exposure responses. For physiological relevance, results from experiments using models for cell cycle control and apoptosis in Vitro will be verified by inhalation studies using mice. Finally, to test the contributions of specific proteins such as p53, CKIS, and other candidate cell cycle regulators in cell cycle activation and/or apoptosis by asbestos and N02, inhalation studies will be performed in transgenic mice lacking specific genes of interest. Dissection of the role of cell cycle and survival regulators in proliferative and apoptotic responses to the combined effects of asbestos and N02 may lead to new biomarkers for exposure of the human lung to chemical mixtures.

描述 人肺暴露于环境颗粒和气体 有助于多种疾病，包括肺纤维化和 癌症。 我们的研究小组的先前工作表明，石棉， 活性氧（ROS）和反应性氮种（RN）触发 肺目标细胞中的特定细胞信号通路，导致 转录因子（例如AP-1和NF-KB）的激活。 这些和其他 转录因子参与细胞决策，导致 肺部疾病开始涉及的表型变化。 扩展 我们对化学和物理混合物的细胞反应的理解 代理商，我们建议研究石棉石棉和氮的影响 二氧化碳（NO2），无论是单独还是在三个暴露端点上： 细胞存活，细胞周期进展和凋亡。 首先，我们会的 表征大鼠肺上皮（RLE）细胞和大鼠肺的反应 关于石棉和/或N02的成纤维细胞（RLF）激活 转录因子AP-1，NF-KB和E2F及其下游目标 基因。 激活细胞周期蛋白依赖性激酶（CDK），其代谢 蛋白质抑制剂（即CKIS P15，PL6，PL8，P2L和P27），并且 视网膜母细胞瘤家族蛋白（PRB和PL3O）的磷酸化将为 研究为细胞周期进程的调节剂。 细胞成像技术， 流式细胞仪和蛋白酶的激活将用于测量凋亡 回答。 显性调节分子的瞬时表达 将用于剖析暴露反应的机制。 用于生理 相关性，实验使用模型进行细胞周期控制和 通过使用小鼠吸入研究，可以在体外凋亡。 最后，测试特定蛋白质（例如p53，ckis）的贡献 和其他候选细胞周期调节剂在细胞周期激活和/或 石棉和N02的凋亡，将进行吸入研究 缺乏特定感兴趣基因的转基因小鼠。 解剖角色 增殖和凋亡中的细胞周期和生存调节剂 对石棉和N02的综合作用的响应可能会导致新的 人类肺暴露于化学混合物中的生物标志物。

项目成果

The COOH terminus of p18INK4C distinguishes function from p16INK4A.

p18INK4C 的 COOH 末端与 p16INK4A 的功能不同。

• 发表时间: 2001
• 期刊: Cancer research.
• 作者: Gump,J;Turner,S;Koh,J
• 通讯作者: Koh,J

Reactive nitrogen species block cell cycle re-entry through sustained production of hydrogen peroxide.

• DOI: 10.1165/rcmb.2002-0112oc
• 发表时间: 2003-01
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Ziqiang Yuan;H. Schellekens;L. Warner;Y. Janssen-Heininger;P. Burch;N. Heintz