Relating DNA Adducts and Toxicogenomics

DNA 加合物与毒理基因组学的关系

• 批准号: 6967377
• 负责人: Paul Vouros
• 金额: $ 45.77万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967377
• 关键词: Relating; DNA; Adducts; Toxicogenomics

DESCRIPTION (provided by applicant): It is generally recognized that a substantial fraction of cancer incidence is of environmental origin, initiated (at least in part) by the covalent binding of chemicals with DNA to form addition products, commonly referred to as DNA adducts. The widely held hypothesis is that, if the system's repair mechanism fails, this damage may have serious biological implications including the accumulation of genetic mutations and the onset of cancer. However, the complete relationship between DNA adducts formation and cancer development in humans is not fully understood. This is, in part, because of the low levels at which adducts are found in affected tissues, the difficulties associated with their analysis and lack of knowledge about the role of genetic predisposition on the repair or other physiological responses subsequent to adduct formation. In recent years, toxicogenomics has developed into a sophisticated area of research focused on understanding how toxicant-induced effects on cells, including DNA and protein adduct formation and interaction with receptor molecules and cell membranes, are translated into cellular responses such as toxicity, abnormal growth and differentiation, mutation, apoptosis and carcinogenesis. The characterization of the human genome and recent advances in microarray technologies now offer unique opportunities for research to understand the link between exposure to environmental carcinogens and global genome functions in cells from living organisms. In this program, we propose to capitalize on the unique strengths of two collaborating laboratories in the areas of trace level analysis of DNA adducts by capillary HPLC-electrospray ionization mass spectrometry (PV) and microarray technology, cellular biology and toxicogenomics (HZ) to generate comprehensive hypotheses that relate tumor growth with mutations initiated by exposure to smoking or other toxic environmental agents. It is hoped that, ultimately, the type of data generated in this study may be used for exposure monitoring and risk assessment that will help transform toxicology into a predictive science.

描述（由申请人提供）：通常认识到，很大一部分癌症发病率是环境起源，通过化学物质与DNA的共价结合形成添加产物，通常称为DNA加合物。广泛持有的假设是，如果系统的修复机制失败，则这种损害可能具有严重的生物学意义，包括遗传突变的积累和癌症的发作。但是，尚不完全了解人类DNA加合物形成与癌症发展之间的完整关系。这部分是由于在受影响的组织中发现加合物的水平较低，因此与它们的分析相关的困难以及缺乏对遗传易感性在修复或加合物形成后其他生理反应的作用的知识。近年来，毒物组学已发展为一个复杂的研究领域，重点是了解毒物诱导的对细胞的影响，包括DNA和蛋白质加合物形成以及与受体分子和细胞膜的相互作用，被翻译成毒性，异常生长和分化，突变，突变，肾上腺异化和癌症等细胞反应。现在，人类基因组的表征和微阵列技术的最新进展为研究提供了独特的机会，可以理解与环境致癌物的暴露与活生物体中细胞中全球基因组功能之间的联系。在该计划中，我们建议通过毛细管HPLC-电喷雾电离质谱法（PV）和微阵列技术，细胞生物学和毒性生物学和毒性基因组学（HZ）的全面型号的毒品或毒物的发展，从而使蛋白质的发展剂促进了毒物的其他假设，从而利用了蛋白质的发展，从而利用了毒物的其他启动，从而利用了蛋白质的发展，从而利用了蛋白质的发展，从而利用了蛋白质的发展，从而利用了蛋白质的发展，从而利用了蛋白质的发展，从而利用了蛋白质的发展，从而利用了蛋白质的发展，从而利用了蛋白质的发展，从而利用了蛋白质的发展，从而利用了蛋白质的发展，从而利用了蛋白质的发展，在该计划中利用了两个合作实验室的独特优势。希望最终，本研究产生的数据类型可以用于暴露监测和风险评估，这将有助于将毒理学转化为预测科学。