Project 1: Assessment of the Health Effects of N-Nitrosamines and Development of Disease Mitigation Strategies

项目 1：N-亚硝胺对健康的影响评估和疾病缓解策略的制定

• 批准号: 10687974
• 负责人: Bevin P. Engelward
• 金额: $ 56.31万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687974
• 关键词: Address; Animals; Biological; Biology; Biosensor; Carcinogens; Cells; Chemical Engineering; Chemicals; Coal; Collaborations; Communities; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Repair; DNA Repair Disorder; DNA Sequence Alteration; DNA glycosylase; Data; Data Analyses; Development; Devices; Dimethylnitrosamine; Disease; Dose; Educational Curriculum; Educational process of instructing; Ensure; Environment; Environmental Policy; Exposure to; Food; Genetic Engineering; Genetically Engineered Mouse; Goals; Hazardous Chemicals; Health; Human; In Vitro; Induced Mutation; Intervention; Knowledge; Longitudinal Studies; Machine Learning; Malignant Neoplasms; Measures; Metabolic; Methods; Methyltransferase; Mission; Molecular; Municipalities; Mus; Mutagens; Mutation; Mutation Detection; N-Methylaspartate; N-nitrosodimethylamine; National Institute of Environmental Health Sciences; Nitrosamines; Nitroso Compounds; Organism; Persons; Pharmaceutical Preparations; Positioning Attribute; Predisposition; Probability; Probiotics; Propylamines; Public Health; Research; Research Activity; Research Support; Risk; Scientist; Serinus; Source; Structure; Superfund; System; Technology; Toxic effect; Training; Transgenes; Tribes; Water; Work; animation; beneficial microorganism; carcinogenesis; chemical genetics; community engagement; data management; drinking water; experience; gene environment interaction; health assessment; high throughput screening; innovation; mathematical model; member; multiple omics; novel; predictive marker; prevent; program dissemination; programs; remediation; repaired; response; screening; sensor; superfund chemical; superfund site

PROJECT SUMMARY/ABSTRACT – PROJECT 1 N-Nitrosamines include some of the most mutagenic chemicals known to humankind, and they are present at and near Superfund Sites, in drinking water, in food and in drugs. Given their ubiquitous presence and potent mutagenicity, research focused on N-nitrosamines is critical. What is needed are better ways to predict N- nitrosamine-induced disease so that intervention strategies can be developed. A key barrier has been the difficulty of studying long-term low-dose conditions. To overcome this challenge, Project 1 will create ‘canary in a coal mine’ genetically engineered model (C-GEM) mice. The C-GEM mice will harbor genetic mutations in the alkyladenine DNA glycosylase (Aag) and the O6-methylguanine methyltransferase (Mgmt), two of the most important repair activities for NMDA-induced DNA damage. They will also harbor two transgenes for detecting mutations (to be analyzed in collaboration with Project 2). C-GEM mice will be exposed to environmentally relevant levels of NDMA, to be determined by Projects 3 and 4, and systems-level data (to be collected with Project 2) will be merged by the Data Management and Analysis Core (DMAC) to create predictive biomarkers and to better understand mechanisms of disease. Project 1 will also study a probiotic organism shown to suppress NDMA-induced cancer. Finally, Project 1 will also create “Chem-Sense Cells,” a novel cell array-based platform for screening environmentally relevant N-nitrosamines (to be identified by Projects 3 and 4) for their DNA damaging potential. Specific Aim 1 is to leverage the C-GEM mice at a sensitive window of susceptibility to reveal the long-term low-dose impact of NDMA administered under environmentally relevant conditions. Specific Aim 2 is to use chemical-genetics to create Chem-Sense Cells as a novel biosensor for DNA damage induced by N-nitrosamines present at Superfund Sites. Specific Aim 3 is to leverage the C-GEM mice to reveal the biological mechanisms by which probiotics modulate mutation susceptibility via studies of systems-level responses. Trainees will drive the research and will be supported by the Research Experience and Training Coordination Core to ensure optimal professional development. With support from the Community Engagement Core, Project 1 Leaders and trainees will also listen to and work with community members and tribes to develop novel hands-on teaching curricula that explain key concepts in biology that underlie their research activities. Importantly, Project 1 is part of a greater Systems Approach for the entire MIT SRP, for which interactions and interdependencies (supported by the Administrative Core) give rise to impact that is not otherwise possible. This includes using machine learning (in collaboration with the DMAC) to merge research results from this Project with that of other Projects to gain a better understanding of risk. The Administrative Core also promotes the dissemination of this Project’s innovative mouse and cell technologies, and it supports bringing research results to the EPA and other stakeholders in order to maximize impact on public health.

项目摘要/摘要--项目1 N-亚硝胺包括一些人类已知的最具诱变性的化学物质，它们存在于 在超级基金网站附近，在饮用水、食品和药品中。鉴于它们无处不在的存在和强大的 致突变性，对N-亚硝胺的研究至关重要。现在需要的是更好的方法来预测N- 亚硝胺诱发的疾病，从而可以制定干预策略。一个关键的障碍是 研究长期低剂量条件的困难。为了克服这一挑战，项目1将创建“金丝雀” 一个煤矿的基因工程模型(C-GEM)小鼠。C-GEM小鼠将在 烷基腺嘌呤DNA糖基酶(AAG)和O6-甲基鸟嘌呤甲基转移酶(MGMT)是最常见的两种酶 NMDA诱导的DNA损伤的重要修复活动。他们还将携带两个转基因来检测 突变(将与项目2合作分析)。C-GEM小鼠将暴露在环境污染中 NDMA的相关水平，将由项目3和项目4确定，以及系统一级的数据(将与 项目2)将由数据管理和分析核心(DMAC)合并，以创建预测性生物标志物 并更好地了解疾病的机制。项目1还将研究一种益生菌，显示出 抑制NDMA诱发的癌症。最后，项目1还将创建“Chem-Sense Cells”，这是一种基于细胞阵列的新型细胞 筛选与环境有关的N-亚硝胺的平台(将由项目3和4确定) DNA损伤的可能性。具体目标1是在敏感的敏感窗口利用C-GEM小鼠 揭示在与环境相关的条件下使用NDMA的长期低剂量影响。 具体目标2是利用化学遗传学创造化学感觉细胞作为DNA损伤的新型生物传感器 由超级基金站点存在的N-亚硝胺引起的。具体目标3是利用C-GEM小鼠揭示 益生菌通过系统水平研究调节突变敏感性的生物学机制 回应。学员将推动研究，并将得到研究经验和培训的支持 协调核心，以确保最佳的专业发展。在社区参与的支持下 核心、项目1领导人和受训人员还将听取社区成员和部落的意见并与其合作，以制定 新颖的实践教学课程，解释作为其研究活动基础的生物学中的关键概念。 重要的是，项目1是整个麻省理工学院SRP的更大系统方法的一部分，对于这些方法，交互和 相互依存关系(得到行政核心的支持)产生了以其他方式不可能产生的影响。这 包括使用机器学习(与DMAC合作)合并本项目的研究结果 与其他项目的风险进行比较，以更好地了解风险。行政核心也促进了 传播该项目的创新鼠标和细胞技术，并支持带来研究成果 环境保护局和其他利益攸关方，以最大限度地影响公共卫生。