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

基本信息

批准号：
8097655
负责人：
JOHN M ESSIGMANN
金额：
$ 8.5万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8097655
关键词：
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 Damage Data Data Set Detection Development Disease Distal Dose Educational process of instructing Employee Strikes Environment 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 Lesion Life Life Cycle Stages Link Liver Malignant Neoplasms Malignant neoplasm of liver Maps Measurement Measures Metabolic Methodology Modeling Mothers Mus Mutagenesis Mutation Names Neonatal Newborn Animals Newborn Infant Normal Cell Organism Pathway interactions Pattern Pharmacodynamics Phase Play Population Predisposition Primary carcinoma of the liver cells Principal Investigator Proteins Rattus Refractory Regimen Research Resistance Resolution Reverse Transcriptase Polymerase Chain Reaction Risk Risk Assessment Role Route Staging Stream Technology Text Time Tissue Sample Tissues Toxic Environmental Substances Toxin Transcript Transgenes Work accelerator mass spectrometry adduct aflatoxin B1-DNA adduct analytical tool base biological systems cancer cell carcinogenesis disorder risk end stage disease environmental agent environmental toxicology experience fetal human disease in vivo infancy knowledge base male mature animal mouse model prenatal prenatal exposure programs pyridine repaired research study response synergism tool toxicant tumor

项目摘要

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，加合物被认为会驱动将正常细胞转化为癌细胞的基因变化，然后癌细胞生长成肿瘤。因此，加合物可能是人类对癌症易感性的重要决定因素，此外，DNA 损伤剂可以直接或间接地改变与癌症不直接相关的靶标；DNA 损伤剂可能在癌症发生中发挥重要作用。引发或促进许多其他疾病的工作是为了了解 DNA 加合如何与可通过现代分析工具确定的其他生化因素相结合，以确定与年龄和性别相关的环境因素的敏感性差异。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空白。首先，我们将提供 B6C3F1 小鼠在从胎儿到婴儿期和成年期的特定时间点的两性生物网络的高分辨率图，并确定这些网络如何响应 AFB1。其次，我们产生的基因网络数据将被锚定。为了灵敏地检测 DNA 加合物，使用甚至可以检测暴露母亲胎儿中的加合物的工具，将使用加速器质谱 (AMS) 来检查 DNA 加合物的形成和命运。第三，我们将给小鼠施用化学干预剂，即萝卜硫素，我们期望它能够改变代谢网络，从而保护出生前、婴儿和成年动物免受这种环境侵害。我们对 AFB1 的实验将结合对 NTP 数据集中的四种化合物的基因毒性作用进行更有限的研究，这些其他药物包括 4-氨基联苯 (ABP)、2-氨基-1-甲基-6-。苯基咪唑并[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。