PULMONARY ADAPTIVE RESPONSES AND CADMIUM CARCINOGENESIS

肺部适应性反应与镉致癌

• 批准号: 2386259
• 负责人: BETH A HART
• 金额: $ 19.89万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-15 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2386259
• 关键词: DNA damage; apoptosis; cadmium; chemical carcinogen; chemical carcinogenesis; cytokine; enzyme activity; enzyme induction /repression; glutamyltransferase; glutathione transferase; heme oxygenase; laboratory rat; lung neoplasms; malonaldehyde; metallothionein; nutrition related neoplasm /cancer; nutrition related tag; oxidizing agents; phorbols; respiratory epithelium; respiratory function; respiratory toxin; tissue /cell culture; toxicology; transcription factor

DESCRIPTION (Adapted from the Investigator's Abstract): Cadmium is an atmospheric pollutant, a tobacco smoke contaminant, and a human lung carcinogen. The investigators have previously demonstrated that chronic cadmium exposure to both cell lines and whole animal studies leads to the emergence of an epithelial cell sub-population with increased resistance to oxidant induced cell death. This new phenotype is hypothesized to be caused by cadmium induced alterations in gene expression, linked mechanistically to cellular glutathione levels and to a common transcription factor. Some of these resistant cells may exhibit increased proliferation (when exposed to tumor promoters) and are resistant to apoptosis. This could ultimately cause clonal expansion and tumor formation. To test these hypotheses, the investigators propose (1) study Cd- induced expression of known cytoprotectins (metallothione, GSH S-transferase, heme oxygenase-1) and enzymes that increase GSH levels (gamma glutamylcysteine synthetase and gaama glutamyl transpeptidase) in rats; (2) immunolocalize these resistance factors in presumptive lung tumor target sites (alveolar type II cells); (3) establish the role of the Ap-1 transcription factor in lung epithelial cell adaptation to cadmium and cross-tolerance to oxidants; (4) determine if malondialdehyde-DNA adducts form in Cd exposed lung epithelial cells; (5) evaluate the potential link between cadmium induced type II cell proliferation and metallothione (MT) expression; and, (6) determine whether Cd-adapted lung epithelial cells are resistant to normal apoptotic processes by oxidants and cytokines and whether phorbal esters increase the proliferative capacity to grow in culture and soft agar (as a marker for tumor promotion).

描述（改编自调查人员的摘要）：镉是一个 大气污染物，烟草烟雾和人类肺 致癌物。 调查人员以前已经证明了慢性 镉暴露于细胞系和整个动物研究导致 上皮细胞亚群的出现，对 氧化剂诱导细胞死亡。 假设这种新表型是引起的 通过镉诱导的基因表达改变，机械机械链接到 细胞谷胱甘肽水平和公共转录因子。 其中一些 这些抗性细胞可能表现出增加的增殖（当暴露于 肿瘤启动子）并且对凋亡具有抗性。 最终可以 导致克隆膨胀和肿瘤形成。 为了检验这些假设， 研究人员提出（1）研究CD诱导的已知表达 细胞保护素（Metallothione，GSH S-转移酶，血红素加氧酶-1）和 增加GSH水平的酶（γ-谷氨酰胺半胱氨酸合成酶和 大鼠的Gaama谷氨酸转肽酶）； （2）免疫定位这些电阻 推定性肺肿瘤靶位部位（牙槽II型细胞）的因素； （3） 确定AP-1转录因子在肺上皮细胞中的作用 适应镉和对氧化剂的交叉耐受性； （4）确定是否 Cd暴露的肺上皮细胞中形成丙二醛-DNA加合物； （5） 评估镉诱导的II型细胞之间的潜在联系 增殖和金属座（MT）表达； （6）确定是否 CD适应的肺上皮细胞对正常凋亡过程有抗性 通过氧化剂和细胞因子，以及佛体酯是否增加 在培养和软琼脂中生长的增殖能力（作为标志物的标志 肿瘤促进）。