Investigating Toxicity of Airborne Metal Nanoparticles: Mechanisms and Characterization

基于纳米粒子（NP）的技术正在电子、替代能源、化妆品和生物医学等不同领域中找到应用，并且作为新的治疗和诊断工具以及作为有效的药物递送装置具有很大的前景。与此同时，人们越来越担心，人类接触纳米颗粒可能会导致重大的不良毒性影响，需要作为紧急事项进行调查。空气传播的金属基纳米颗粒特别令人关注，因为它们容易悬浮在环境空气中，因此在其生产和使用过程中可能会偶然或意外吸入。吸入的NP在肺区域中具有非常高的沉积效率，并且具有穿透上皮并到达间质部位和循环系统的高倾向。因此，NP暴露可能造成心肺损伤的风险，但这种类型的研究需要基于系统的方法。到目前为止，缺乏适当的细胞-NP暴露系统阻碍了吸入暴露于金属NP的心肺毒性的研究。 我的研究计划的长期目标是通过使用创新的毒理学方法阐明NP毒性的细胞和分子机制，更好地了解空气中基于金属的NP如何与生物系统相互作用。该计划有两个首要目标：i）推进体外毒性测试系统，以更确定地筛选、排名和预测NP的毒性作用; ii）使用毒理基因组学方法识别和表征因果因素和NP毒性。在接下来的五年里，我的短期目标将评估吸入金属纳米颗粒的毒性，并通过提供有关其因果因素和机制的更多信息，优先考虑在动物研究中更深入地使用纳米颗粒。我特别提议：1）阐明NP增强肺部细菌感染的根本原因和机制，以及2）评估肺部NP暴露对心血管系统的影响。 随着这项研究的成功完成，将有许多好处提供（1）HQP独特的培训机会，为一个新的分支的科学（2）关于NP毒性的等级和用于作为成本有效筛选的体内测试的NP的优先级的有价值的信息;（3）了解NP暴露产生生物反应的机制，因为这将使我们处于有利地位，以制定设计安全NP的策略。

Nanoparticle (NP, -based technologies are finding applications in fields as diverse as electronics, alternative energy, cosmetics and biomedicine, and hold great promise as new therapeutic and diagnostic tools and as effective drug delivery devices. At the same time, rising concerns that human exposure to NPs may lead to significant adverse toxic effects need to be investigated as a matter of urgency. Airborne metal-based NPs are of particular concern because they are readily suspended in ambient air and so can be inhaled incidentally or accidentally throughout their production and use. Inhaled NPs have a very high deposition efficiency in the pulmonary region, and a high propensity to penetrate the epithelium and reach interstitial sites and the circulatory system. It then follows that NP exposure could pose a risk of cardiopulmonary injury, but this type of study requires a systems-based approach. Until now, the lack of an appropriate cell-NP exposure system has hampered the study of the cardiopulmonary toxicity of inhalation exposure to metal NPs. The long-term goal of my research program is to better understand how airborne metal-based NPs interact with biological systems by elucidating the cellular and molecular mechanisms underlying NP toxicity using an innovative toxicology approach. This program has two overarching objectives: to i) advance an in vitro toxicity testing system to screen, rank and predict with greater certainty the toxic effects of NPs and ii) identify and characterize the causal factors and NP toxicity using a toxicogenomic approach. Over the next five years, my short-term objectives will assess the toxicity of inhaled metal NPs and prioritize NPs for more in depth in animal studies by providing more information on its causal factors and mechanisms. I specifically propose to: 1) elucidate the underlying causes and mechanisms by which NPs enhance lung bacterial infection and 2) assess the effects of pulmonary NP exposure on the cardiovascular system. With successful completion of this research, there will be many benefits providing (1) HQP with unique training opportunities for a new branch of science (nanotoxicology); (2) valuable information on the rank of NP toxicity and prioritization of NPs for in vivo testing as a cost-effective screening; (3) understanding of the mechanisms by which NP exposures produce biological responses as this will put us in a strong position to develop strategies to design safe NPs.