Genotoxic effects of butadiene and human cytomegalovirus

丁二烯和人类巨细胞病毒的基因毒性作用

• 批准号: 6260980
• 负责人: THOMAS B. ALBRECHT
• 金额: $ 26.67万
• 依托单位: SOUTHERN UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6260980
• 关键词: DNA damage; adduct; cell cycle; cell line; cooperative study; cytomegalovirus; diene; environmental toxicology; minority institution research support; mutagens; oncoprotein p21; protein degradation; toxicant interaction; virus infection mechanism

Although human cytomegalovirus (HCMV) has demonstrated oncogenic potential and the ability to enhance the level of genetic damage induced by genotoxic chemicals, the precise mechanisms through which this common virus exerts these effects is unknown. It is known that HCMV induces robust mitogenic signaling, but there is little information on how cell cycle perturbation by HCMV may contribute to the increased susceptibility of infected cells to chemical-induced genotoxicity. As part of our ongoing investigation of the mechanisms through which HCMV affects cell cycle control, we have identified the activation of multiple pathways for the proteolytic degradation of p21cip1. The proposed studies will test the hypothesis that HCMV infection affects the sensitivity of cells to butadiene-induced genetic damage, particularly through inhibition of the cell cycle arrest response to DNA damage. The effect of HCMV infection on DNA adduct formation, mutation frequency and spectrum, and cell cycle progression in cells treated with butadiene or its metabolites will be investigated in human lung cells and peripheral blood lymphocytes, and in hamster V79 cells. The proteolytic degradation of p21/cip1 and inhibition of the DNA damage-induced cell arrest will be investigated in the butadiene/HCMV-treated cells. The effect of HCMV on butadiene-induced DNA adduct formation will be studied in collaboration with the Lloyd and Van Houten laboratories using quantitative PCR assays. Mutation will be studied at the hprt locus in a collaborative study with the Ward and Postlethwait laboratories. The Muganda and Albrecht laboratories will collaborative in studying the effect of HCMV infection on p53, p21cip1, and cell cycle progression.

虽然人类巨细胞病毒(HCMV)已经显示出致癌潜力和增强遗传毒性化学物质诱导的遗传损伤水平的能力，但这种常见病毒发挥这些作用的确切机制尚不清楚。已知的是，巨细胞病毒可以诱导强大的有丝分裂信号，但关于巨细胞病毒对细胞周期的干扰如何导致感染细胞对化学诱导的遗传毒性的敏感性增加的信息很少。作为我们正在进行的巨细胞病毒影响细胞周期控制机制的研究的一部分，我们已经确定了p21cip1蛋白降解的多条途径的激活。拟议的研究将检验这一假设，即HCMV感染影响细胞对丁二烯诱导的遗传损伤的敏感性，特别是通过抑制细胞对DNA损伤的细胞周期停滞反应。人巨细胞病毒感染对丁二烯或其代谢产物处理的细胞DNA加合物的形成、突变频率和谱以及细胞周期进程的影响，将在人肺细胞和外周血淋巴细胞以及仓鼠V79细胞中进行研究。在丁二烯/HCMV处理的细胞中，将研究p21/cip1的蛋白降解和对DNA损伤诱导的细胞停滞的抑制。将与Lloyd和Van Houten实验室合作，使用定量聚合酶链式反应分析来研究巨细胞病毒对丁二烯诱导的DNA加合物形成的影响。在与Ward和PostlethWait实验室的合作研究中，将对HPRT基因座的突变进行研究。Muganda和Albrecht实验室将合作研究HCMV感染对p53、p21cip1和细胞周期进程的影响。