The Environment as a Variable to Calibrate Mouse Models of Human Disease

描述（由申请方提供）：大多数致癌物与DNA形成共价产物或加合物。加合物被认为是驱动遗传变化的动力，将正常细胞转化为癌细胞，然后再生长成肿瘤。因此，影响加合物形成或去除的因素可能是人类致癌易感性的重要决定因素。此外，损伤DNA的试剂可以修饰与癌症不直接相关的靶标;直接或间接地，DNA损伤试剂可以在引发或促进许多其他疾病中发挥重要作用。下面描述的工作是为了了解DNA内收如何与其他生物化学因素相结合，通过现代分析工具确定，以确定与年龄和性别相关的环境因子敏感性的差异。这项工作的主要重点是黄曲霉毒素B1（AFB 1），一种重要的人类肝脏致癌物质，与大多数肝细胞癌病例有关，特别是当毒素与肝炎病毒协同作用时。我们的工作将解决四个知识差距。首先，我们将提供B6 C3 F1小鼠从胎儿到婴儿期和成年期的特定时间点的两种性别的生物网络的高分辨率地图，并确定这些网络如何对AFB 1做出反应。其次，我们产生的基因网络数据将被锚定到DNA加合物的灵敏检测，使用一种工具，甚至可以检测暴露母亲的胎儿中的加合物。加速器质谱（AMS）将用于检查DNA加合物在生命的敏感和抗性阶段的形成和命运。第三，我们将向小鼠施用化学干预剂萝卜硫素，我们预期其将以保护出生前、婴儿和成年动物免受这种环境损害的方式改变代谢网络。最后，我们的实验与黄曲霉毒素B1将与一个更有限的调查的遗传毒性作用的四个化合物从NTP数据集。这些附加药物包括4-氨基联苯（ABP）、2-氨基-1-甲基-6-苯基咪唑[4，5-B]吡啶（PhIP）、丙烯酰胺和17-雌二醇（E2）。这项研究的一个重要目标是开发一系列新的生物标志物，这些生物标志物可以应用于小鼠模型，以及后来用于预测环境因子对人类影响的其他模型。

DESCRIPTION (provided by applicant): Most carcinogens form covalent products, or adducts, with DNA. Adducts are believed to drive the genetic changes that convert normal cells into cancer cells, which then outgrow into a tumor. Factors that influence the formation or removal of adducts, therefore, are likely to be important determinants of human susceptibility to carcinogenesis. Moreover, agents that damage DNA can modify targets not directly relevant to cancer; directly or indirectly, DNA damaging agents may play important roles in initiating or promoting a host of other diseases. The work described below is an effort to understand how DNA adduction integrates with other biochemical factors, determinable by modern analytical tools, to define the differences in sensitivity to environmental agents that are associated with age and gender. The main focus of the work deals with aflatoxin B1 (AFB1), an important human liver carcinogen that is associated with most cases of hepatocellular carcinoma, especially when toxin works in concert with hepatitis viruses. Our work will address four gaps in knowledge. First, we shall provide a high resolution map of the biological networks of both genders of the B6C3F1 mouse at specific time points from fetus through infancy and adulthood and determine how those networks respond to AFB1. Second, the gene network data we produce will be anchored to sensitive detection of DNA adducts, using a tool that will even detect adducts in the fetus of an exposed mother. Accelerator Mass Spectrometry (AMS) will be used to examine the formation and fate of DNA adducts at sensitive and resistant stages of life. Third, we shall administer to mice a chemo-interventive agent, sulphoraphane, that we expect will alter metabolic networks in a manner that will protect pre- born, infant and adult animals from this environmental insult. Finally, our experiments with AFB1 will be coupled with a more limited investigation of the genotoxic effects of four compounds from the NTP data set. These additional agents include4-aminobiphenyl (ABP), 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), acrylamide and 17¿-estradiol (E2). An important goal of this research is the development of a host of new biomarkers that can be applied to the mouse model, and later other models that are used to predict the impact of environmental agents on humans.