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

项目总结/摘要-项目1 N-亚硝胺包括人类已知的一些最具诱变性的化学物质，它们存在于 以及超级基金站点附近的饮用水、食物和药物中。由于它们无处不在， 致突变性，研究重点是N-亚硝胺是至关重要的。我们需要的是更好的方法来预测N- 亚硝胺引起的疾病，以便制定干预策略。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“金丝雀在 一种煤矿“基因工程模型”（C-GEM）小鼠。C-GEM小鼠将携带基因突变， 烷基腺嘌呤DNA糖基化酶（Aag）和O 6-甲基鸟嘌呤甲基转移酶（Mgmt），两个最重要的 对NMDA诱导的DNA损伤具有重要的修复活性。他们还将携带两种转基因， 突变（将与项目2合作进行分析）。C-GEM小鼠将暴露于环境中 NDMA的相关级别，由项目3和4确定，以及系统级数据（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 更好地了解疾病的机制。项目1还将研究一种益生菌， 抑制NDMA诱导的癌症。最后，项目1还将创建“化学感测细胞”，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（将由项目3和4确定）的平台， DNA损伤潜力具体目标1是在敏感窗口利用C-GEM小鼠 揭示在环境相关条件下给予NDMA的长期低剂量影响。 具体目标二是利用化学遗传学方法构建一种新型的DNA损伤生物传感器--化学传感细胞 由超级基金所在地的N-亚硝胺引起。具体目标3是利用C-GEM小鼠来揭示 益生菌通过系统水平的研究调节突变易感性的生物学机制 应答学员将推动研究，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领导人和学员还将听取并与社区成员和部落合作， 新颖的实践教学课程，解释生物学中的关键概念，作为其研究活动的基础。 重要的是，项目1是整个MIT SRP的更大系统方法的一部分， 相互依存（由行政核心支持）产生的影响是不可能的。这 包括使用机器学习（与DMAC合作）来合并该项目的研究结果 以更好地了解风险。行政核心还促进 传播该项目的创新小鼠和细胞技术，并支持将研究成果 环保署和其他利益相关者，以最大限度地影响公众健康。

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.