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

环境作为校准人类疾病小鼠模型的变量

• 批准号: 7351205
• 负责人: JOHN M ESSIGMANN
• 金额: $ 54.44万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7351205
• 关键词: 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; 4-biphenylamine; Acrylamide; Acrylamides; Address; Adult; Affect; Aflatoxin B1; Aflatoxins; Age; Animal Cancer Model; Animal Model; Animals; Applications Grants; Biochemical; Biochemical Genetics; Biochemical Pathway; Biological; Biological Assay; Biological Markers; Carcinogens; Cells; Chemicals; Clinical; Coupled; Cytochrome P450; DNA; DNA Adduction; DNA Adducts; DNA Binding; DNA Damage; Data; Data Set; Detection; Development; Disease; Distal; Dose; Educational process of instructing; Employee Strikes; Environment; Environmental Impact; Enzymes; Epidemiologic Studies; Epidemiology; Estradiol; Etiology; Excision; Female; Fetus; Figs - dietary; Gender; Gene Expression; Genes; Genome; Goals; Graph; Hand; Hepatitis B; Hepatitis Viruses; Hepatocarcinogenesis; Human; Individual; Infant; Infectious Agent; Intervention; Investigation; Kinetics; Knowledge; Label; Lesion; Life; Life Cycle Stages; Link; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Maps; Measurement; Measures; Metabolic; Metabolism; Methodology; Methods; Modeling; Molecular Profiling; Mothers; Mus; Mutagenesis; Mutation; Neonatal; Newborn Animals; Newborn Infant; Normal Cell; Organism; Pathway interactions; Patient currently pregnant; Pattern; Pharmacodynamics; Phase; Play; Population; Predisposition; Primary carcinoma of the liver cells; Proteins; Rate; Rattus; Refractory; Research; Resistance; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Assessment; Role; Route; Staging; Structure; Sulforaphane; System; Technology; Text; Thinking; Time; Tissue Sample; Tissues; Toxic Environmental Substances; Toxicokinetics; Toxin; Transcript; Transgenes; Treatment Protocols; Week; Work; accelerator mass spectrometry; adduct; aflatoxin B1-DNA adduct; analytical tool; base; cancer cell; carcinogenesis; cruciferous vegetable; disorder risk; environmental agent; environmental toxicology; experience; fetal; human disease; in vivo; infancy; interest; knowledge base; male; mature animal; mouse model; prenatal; prenatal exposure; programs; pup; pyridine; repaired; research study; response; synergism; tool; toxicant; tumor

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.

描述（由申请人提供）：大多数致癌物与DNA形成共价产物或加合物。加合物被认为可以驱动基因变化，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对致癌易感性的重要决定因素。此外，破坏DNA的药物可以改变与癌症没有直接关系的目标；DNA损伤因子可能直接或间接地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理解DNA内合如何与其他生化因素结合，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 (AFB1)，这是一种重要的人类肝癌致癌物，与大多数肝细胞癌有关，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缺口。首先，我们将提供从胎儿到婴儿期和成年期特定时间点的B6C3F1小鼠两性生物网络的高分辨率地图，并确定这些网络如何对AFB1作出反应。其次，我们产生的基因网络数据将被固定在DNA加合物的敏感检测上，使用一种工具，甚至可以检测暴露在母体中的胎儿的加合物。加速器质谱（AMS）将用于检查DNA加合物在生命敏感和耐药阶段的形成和命运。第三，我们将给老鼠注射一种化学干预剂，磺胺硫素，我们希望它能改变代谢网络，以保护早产儿、婴儿和成年动物免受这种环境的伤害。最后，我们对AFB1的实验将与来自NTP数据集的四种化合物的遗传毒性作用的更有限的研究相结合。这些附加试剂包括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记物，这些生物标记物可以应用于小鼠模型，以及后来用于预测环境因素对人类影响的其他模型。