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：
8212454
负责人：
JOHN M ESSIGMANN
金额：
$ 56.54万
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 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212454
关键词：
2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine 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 Gender Gene Expression Gene Mutation Genes Genome Goals Graph Hepatitis B Hepatitis C 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 infant animal knowledge base male mature animal mouse model prenatal prenatal exposure programs 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（由适用提供）：大多数致癌物与DNA形成共价产物或加合物。据信添加可以驱动将正常细胞转化为癌细胞的遗传变化，然后将其长于肿瘤。因此，影响形成或去除加合物的因素可能是人类对癌变敏感性的重要决定者。此外，损害DNA的药物可以修改与癌症无直接相关的靶标的。直接或间接地，DNA破坏药物可能在发起或促进许多其他疾病中起重要作用。下面描述的工作是为了了解DNA添加如何与其他分析工具确定的其他生化因素整合在一起，以定义与年龄和性别相关的环境药物的敏感性差异。这项工作的主要重点涉及黄曲霉毒素B1（AFB1），这是一种重要的人肝癌，与大多数肝细胞癌病例有关，尤其是当毒素与肝炎病毒合作时。我们的工作将解决知识的四个差距。首先，我们将在从胎儿到婴儿期和成年期的特定时间点上提供B6C3F1小鼠两种性别的生物网络的高分辨率图，并确定这些网络对AFB1的反应。其次，我们产生的基因网络数据将锚定在对DNA加合物的敏感检测中，该工具甚至可以检测到暴露母亲的胎儿中的加合物。加速器质谱法（AMS）将用于检查在敏感和抗性阶段的DNA加合物的形成和命运。第三，我们将向小鼠进行化学干预剂硫酸硫烷，我们期望以一种可以保护前出生，婴儿和成年动物免受这种环境侮辱的方式改变代谢网络。最后，我们对AFB1的实验将与NTP数据集对四种化合物的遗传毒性作用的投资更加有限。这些其他药物包括4-氨基苯基（ABP），2-氨基-1-甲基-6-苯基咪唑唑[4,5-B]吡啶（PHIP），丙烯酰胺和17？-Ertadiol（E2）。这项研究的一个重要目标是开发可应用于小鼠模型的许多新生物标志物，以及后来用于预测环境药物对人类影响的其他模型。