Genetic Factors that Influence Arsenic Toxicity

影响砷毒性的遗传因素

• 批准号: 10093045
• 负责人: Gary A Churchill
• 金额: $ 71.72万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093045
• 关键词: Address; Affect; Animal Model; Animal Testing; Animals; Arsenic; Benchmarking; Biochemical; Biological; Biological Assay; Biological Markers; Cell Line; Cell physiology; Cells; Cellular Assay; Chemical Exposure; Chemicals; Chromosome Mapping; Clinical; Complex; Computer Models; DNA Methylation; Data; Dose; Environment; Environmental Pollutants; Environmental Risk Factor; Evaluation; Event; Experimental Designs; Exposure to; Fibroblasts; Functional disorder; Genes; Genetic; Genetic Markers; Genetic Variation; Genotoxic Stress; Genotype; Goals; Health; Human; In Vitro; Individual; Intervention; Intrinsic factor; Kidney; Lead; Life; Link; Malignant Neoplasms; Maps; Measurement; Measures; Metabolism; Methods; Modeling; Molecular; Molecular Genetics; Mouse Cell Line; Mus; Organ; Outcome; Oxidative Stress; Pathway interactions; Phenotype; Physiological; Population; Population Heterogeneity; Predisposition; Primary Cell Cultures; Proximal Kidney Tubules; Reproducibility; Research Design; Resistance; Resources; Risk; Risk Assessment; Role; Safety; Sample Size; Series; Soil; Statistical Data Interpretation; Statistical Methods; System; Testing; Tissues; Toxic effect; Toxicology; Translating; Validation; Variant; Whole Organism; adverse outcome; base; cell type; clinical translation; cohort; cytotoxicity; drinking water; experimental study; genetic analysis; genetic approach; genomic locus; genotoxicity; ground water; high throughput screening; improved; in vivo; in vivo Model; individual variation; insight; metabolomics; mouse model; novel; novel strategies; outcome prediction; population based; predictive marker; renal damage; response; safety assessment; sex; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT This project is a proof of principle of systems toxicology, a new approach to chemical safety evaluation that integrates molecular, cellular, and physiological data in the context of a genetically diverse animal model to develop testable hypotheses about the key molecular events leading to adverse outcomes following chemical exposure. The project aims to capitalize on the potential of two powerful population-based model organism resources, the Collaborative Cross (CC) and Diversity Outbred (DO) mice, to study the role of genetics in conferring susceptibility to chemical exposures. Through an integrated set of experiments using arsenic exposure in mice and cell lines, the molecular genetic basis of toxicological responses will be evaluated. This project will test the hypothesis that genetic analysis in the context of a quantitative environmental perturbation will reveal multiple, novel, and diverse biochemical networks that respond to chemical exposure. The proposed integrated set of experiments will enable the discovery and validation of adverse outcome pathways through three specific aims. Aim 1 will evaluate study designs for animal testing with genetically diverse DO mice including sample size requirements for toxicity evaluation. G x E genetic loci will be mapped and incorporated into predictive computational models, and testable hypotheses will be proposed for validation. Aim 2 will conduct a parallel, population-level arsenic exposure study of in vitro primary cell cultures to identify genetic factors underlying susceptibility and resistance using physiologically informative cellular phenotypes. The data generated in the in vitro arsenic exposure study will allow determination of the extent to which cytotoxicity, genotoxicity, and oxidative stress in cellular assays are physiologically informative for the discovery of molecular pathways that drive susceptibility and/or response in the whole organism. Aim 3 will identify key mechanisms in renal arsenic toxicity. This study will generate a model for the effect of arsenic exposure on the kidney to predict outcomes that are contingent on genetic background. Collectively, this new approach to toxicology using DO mice will address fundamental biological questions by combining chemical interventions with genetic variation. It will establish causal pathways across multiple levels of molecular and physiological outcomes to yield results with relevance to clinical translation.

项目概要/摘要 该项目是系统毒理学原理的证明，是一种化学安全评估的新方法， 在遗传多样性动物模型的背景下整合分子、细胞和生理数据 制定关于导致化学药物不良后果的关键分子事件的可检验假设 接触。该项目旨在利用两种强大的基于群体的模型生物的潜力 资源，协作杂交（CC）和多样性远交（DO）小鼠，以研究遗传学在 赋予对化学物质暴露的敏感性。通过一系列使用砷的综合实验 在小鼠和细胞系中暴露后，将评估毒理学反应的分子遗传基础。这 该项目将测试以下假设：定量环境扰动背景下的遗传分析 将揭示对化学暴露做出反应的多种、新颖且多样化的生化网络。这 拟议的一组综合实验将能够发现和验证不良结果途径 通过三个具体目标。目标 1 将评估使用遗传多样性 DO 进行动物测试的研究设计 小鼠，包括毒性评估的样本量要求。 G x E 遗传位点将被绘制并 纳入预测计算模型，并将提出可测试的假设进行验证。 目标 2 将在体外原代细胞培养物中进行平行的群体水平砷暴露研究，以确定 使用生理信息细胞表型来研究易感性和耐药性背后的遗传因素。 体外砷暴露研究中生成的数据将有助于确定砷暴露的程度 细胞分析中的细胞毒性、基因毒性和氧化应激为 发现驱动整个生物体敏感性和/或反应的分子途径。目标3将 确定砷肾毒性的关键机制。这项研究将建立一个砷影响的模型 肾脏暴露来预测取决于遗传背景的结果。总的来说，这个新 使用 DO 小鼠的毒理学方法将通过结合化学方法来解决基本的生物学问题 遗传变异的干预措施。它将建立跨多个分子水平和 生理结果产生与临床转化相关的结果。