Development of a Screening Tool for Nanotoxicology

提案标题：开发纳米毒理学筛选工具首席研究员：Valerie Leppert研究所：加州大学-梅赛德分校提案编号：CBET-0854574该奖项由2009年美国复苏和再投资法案(公共法律第111-5号)资助。提出了一个环境和工程纳米相呼吸毒性的模型，该模型基于表面过渡金属杂质与肺细胞外衬里液体的成分反应产生的活性氧物种(ROS)，以及随后的脂质过氧化和炎症介质的产生。这项拟议的研究将寻求验证该模型，并调查颗粒特征和剂量的作用。具体目标包括确定颗粒大小、形状、表面过渡金属和剂量对呼吸毒性和/或肺泡大时相呼吸爆发的影响；以及确定过氧化氢的产生和/或脂质过氧化产物是否参与亚致死浓度的痕量金属参与炎症和纤维化介质的产生的机制。为了了解呼吸毒性的作用机制，所研究的纳米相的完整表征是必不可少的，这将通过电感耦合等离子体质谱、扫描和透射电子显微镜以及高空间分辨率的电子能量损失和能量色散X射线光谱分析来完成。模型确认后，将研究巨噬细胞炎症介质产生的体外筛选试验，该试验可用于预测自然发生的和工程颗粒引起的肺部炎症。将研究的相包括环境二氧化硅、合成二氧化硅、二氧化钛和单壁碳纳米管。拟议的活动将有助于实现若干教育和外联目标。拟议工作的研究成果将在加州大学默塞德分校S通识教育核心课程(这些课程是加州大学默塞德分校所有学生的必修课)的纳米技术和空气污染讲座中展示。由PI导师组成的学生工程服务学习团队也将把研究结果纳入团队为城堡科技中心设计的纳米技术展品中。CSTC是当地的科学发现博物馆，默塞德和周边县的大多数中学生都会去参观(该地区的人口约50%是西班牙裔)。建议的工作将利用加州大学默塞德？S成像和显微镜设施在硬-软电子显微镜方面的新能力，在建议的工作过程中开发的新显微技术将在PI教授的电子显微镜课程中传播。此外，PI和共同PI将通过UCM参与的NSF NSEC集成纳米机械系统项目将本科生纳入拟议的研究。加州大学默塞德分校是一家西班牙裔服务机构，是加州大学第10个也是最新的校区，拥有约50%的少数族裔学生。PIS致力于让代表不足和非传统的学生参与科学和工程研究和教育

Proposal Title: Development of a Screening Tool for NanotoxicologyPrincipal Investigator: Valerie Leppert Institution: University of California - MercedProposal No: CBET- 0854574 This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).A model is proposed for the respiratory toxicity of ambient and engineered nanophases based on production of reactive oxygen species (ROS) from the reaction of surface transition metal impurities with components of the lung extracellular lining fluid (ELF), and subsequent lipid peroxidation and production of inflammatory mediators. The proposed research will seek to verify the model and investigate the role of particle characteristics and dose. Specific objectives include determination of the effect of particle size, shape, surface transition metals, and dose on respiratory toxicity and/or the alveolar macrophase respiratory burst; and determination of whether hydrogen peroxide production and/or lipid peroxidation products are involved in the mechanism through which trace metals at sub-lethal concentrations are involved in the production of inflammatory and fibrogenic mediators. Complete characterization of the nanophases investigated is essential in order to understand the mechanisms at work in respiratory toxicity, and this will be accomplished by ICP-MS, and scanning and transmission electron microscopy in concert with high spatial-resolution electron energy-loss and energy-dispersive X-ray spectroscopy. Following confirmation of the model, an in vitro screening assay for macrophage inflammatory mediator production that could be used to predict lung inflammation caused by naturally occurring and engineering particles will be investigated. Phases that will be investigated include ambient silica, synthetic silica, titanium dioxide, and SWCNTs. The proposed activities will contribute to several educational and outreach objectives. Research results from the proposed work will be presented in nanotechnology and air pollution lectures given by the PI and co-PI in UC Merced?s General Education Core Courses (these course are required for all UC Merced students). A student Engineering Service Learning team that the PI mentors will also incorporate results from the research into nanotechnology exhibits that the team designs for the Castle Science and Technology Center. CSTC is a local science discovery museum that most middle school students in Merced and surrounding counties visit (the population of the area is ~50% Hispanic). New capabilities in hard-soft electron microscopy at UC Merced?s Imaging and Microscopy Facility will be utilized for the proposed work, and new microscopy techniques developed in the course of the proposed work will be disseminated in the electron microscopy courses that the PI teaches. In addition, the PI and co-PI will incorporate undergraduate students in the proposed research through the NSF NSEC Center Of Integrated Nanomechanical Systems program that UCM participates in. UC Merced, a Hispanic Service Institution, is the 10th and newest campus of the University of California, with a ~50% minority student population. The PIs are committed to the engagement of underrepresented and nontraditional students in science and engineering research and education