Relating DNA Adducts and Toxicogenomics

描述（由申请人提供）：人们普遍认为，癌症发病率的很大一部分是环境来源的，由化学品与DNA共价结合形成加成产物（通常称为DNA加合物）引发（至少部分）。普遍认为的假设是，如果系统的修复机制失败，这种损害可能具有严重的生物学意义，包括基因突变的积累和癌症的发生。然而，DNA加合物形成与人类癌症发展之间的完整关系尚未完全了解。这部分是因为在受影响的组织中发现的加合物水平低，与其分析相关的困难以及缺乏关于遗传易感性对加合物形成后的修复或其他生理反应的作用的知识。近年来，毒理基因组学已发展成为一个复杂的研究领域，重点是了解毒物诱导的细胞效应，包括DNA和蛋白质加合物的形成以及与受体分子和细胞膜的相互作用，如何转化为细胞反应，如毒性，异常生长和分化，突变，凋亡和致癌。人类基因组的特征和微阵列技术的最新进展现在为研究了解暴露于环境致癌物与活生物体细胞中的全球基因组功能之间的联系提供了独特的机会。在这个项目中，我们建议利用两个合作实验室在毛细管HPLC-电喷雾电离质谱（PV）和微阵列技术，细胞生物学和毒理基因组学（HZ）的DNA加合物痕量水平分析领域的独特优势，以产生全面的假设，将肿瘤生长与暴露于吸烟或其他有毒环境因子引发的突变联系起来。希望最终，本研究中生成的数据类型可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。

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.