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：
8895929
负责人：
JOHN M ESSIGMANN
金额：
$ 31.59万
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895929
关键词：
Adolescent Adult Affect Aflatoxin B1 Animal Model Animals Antioxidants Applications Grants Benzene Carcinogens Cell physiology Cells Chemicals Complex Consensus Sequence DNA DNA Adduction DNA Damage DNA Repair Pathway DNA Sequence DNA-Directed DNA Polymerase Development Diagnostic Neoplasm Staging Disease Drug resistance Environment Environmental Carcinogens Event Exposure to Female Frequencies Gene Expression Genes Genetic Genome Genomic DNA Genomic Segment Genomics Goals Grant Health Hepatitis B Hepatocarcinogenesis Human Incidence Inflammation Intervention Investigation Liver Liver neoplasms Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Malondialdehyde Measures Modeling Modification Mus Mutagenesis Mutagens Mutation Nodule Normal Cell Pathway interactions Pattern Phase Phenotype Predisposition Primary carcinoma of the liver cells Process Production Protocols documentation Public Health Recording of previous events Risk Risk Factors Role Source Staging Technology Testing Time Tissues Transgenes Transgenic Organisms Tumor Promoters Tumor stage Variant Work adduct design disorder prevention environmental agent environmental carcinogenesis environmental chemical human disease male mouse model mutant next generation sequencing non-genetic postnatal premature programs radiation resistance repaired research study sex therapy design tool tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Exposure to genotoxic carcinogens via both external and internal environments increases risks for major human cancers. Such chemicals form covalent adducts with DNA, which are thought to create a complex program of genetic change acting as the initiating event in malignant transformation and contributing to subsequent tumor progression. Adducts can also disrupt formation or maintenance of normal genome modifications, altering gene expression in affected tissues. Factors that influence formation or repair of adducts are thus likely to be important determinants of human susceptibility to environmental carcinogenesis. We propose an approach to elucidate types of DNA damage and cellular processes responsible for genetic changes that transform normal cells to malignant ones. As a tool, our work focuses on aflatoxin B1 (AFB1), an established risk factor for human hepatocellular carcinoma that strongly elevates risk in synergy with hepatitis B virus infection. As in the human HCC incidence pattern, AFB1 is more potent in males than females, and animals of both sexes are more sensitive as juveniles than as adults. The hypothesis underlying our proposed work is that different quantitative features of mutagenesis (mutation frequencies) or qualitative features (mutational patterns) are determinants of the initiation and promotion phases of tum origenesis. The goal of our work is to characterize these quantitative and qualitative features and define their roles in modulating liver carcinogenesis. Experiments designed to test this hypothesis will employ a newly developed Duplex Sequencing protocol that enables the application of Next-generation sequencing platforms for mutational analysis. Mutation frequencies and spectra will be determined in selected genomic DNAs at stages throughout the tumorigenic process in a mouse model of AFB1-induced liver cancer. These analyses will enable us to determine whether a "mutator phenotype" is acquired during tumor development induced by AFB1, while providing a picture of its variation among different genes. Evidence of mutator phenotypes is seen in many advanced human tumors, and is increasingly considered as a possible source of premature-onset drug or radiation resistance. The types of mutations that we observe will provide hallmarks of the cellular processes that orchestrate the genetic changes during tumorigenesis. Our animal model is well suited to study the time of onset of a mutator phenotype and, of equal importance, for additional studies to investigate interventions that could delay tumor development and drug resistance.

描述（由申请人提供）：通过外部和内部环境接触基因毒性致癌物会增加患主要人类癌症的风险。这些化学物质与 DNA 形成共价加合物，被认为创建了一个复杂的基因变化程序，作为恶性转化的起始事件，并促进随后的肿瘤进展。加合物还可以破坏正常基因组修饰的形成或维持，从而改变受影响组织中的基因表达。因此，影响加合物形成或修复的因素可能是人类对环境致癌的易感性的重要决定因素。我们提出了一种方法来阐明 DNA 损伤的类型和细胞过程，这些过程负责将正常细胞转变为恶性细胞的遗传变化。作为一种工具，我们的工作重点是黄曲霉毒素 B1 (AFB1)，这是一种已知的人类肝细胞癌危险因素，与乙型肝炎病毒感染协同作用会大大提高风险。与人类 HCC 发病模式一样，AFB1 在雄性中比在雌性中更有效，并且男女动物在幼年时都比成年时更敏感。我们提出的工作的假设是，诱变的不同定量特征（突变频率）或定性特征（突变模式）是肿瘤发生的起始和促进阶段的决定因素。我们工作的目标是表征这些定量和定性特征，并确定它们在调节肝癌发生中的作用。旨在检验这一假设的实验将采用新开发的双工测序方案，该方案能够应用下一代测序平台进行突变分析。将在 AFB1 诱导的肝癌小鼠模型的整个致瘤过程的各个阶段确定选定的基因组 DNA 的突变频率和谱。这些分析将使我们能够确定“突变表型”是否是在 AFB1 诱导的肿瘤发育过程中获得的，同时提供不同基因之间变异的图片。在许多晚期人类肿瘤中都可以看到突变表型的证据，并且越来越多地被认为是早发药物或放射抗性的可能来源。我们观察到的突变类型将提供在肿瘤发生过程中协调遗传变化的细胞过程的标志。我们的动物模型非常适合研究突变表型的出现时间，并且同样重要的是，适合进行其他研究以调查可能延迟肿瘤发展和耐药性的干预措施。