Investigating Toxicity of Airborne Metal Nanoparticles: Mechanisms and Characterization

基于纳米颗粒(NP)的技术在电子、替代能源、化妆品和生物医学等领域得到了广泛的应用，并作为新的治疗和诊断工具以及有效的药物输送装置具有巨大的前景。与此同时，对人类暴露于NPs可能导致重大不良毒性影响的担忧日益加剧，需要作为紧急事项进行调查。空气中的金属基NPs特别令人担忧，因为它们很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地被吸入。吸入的纳米颗粒在肺部区域具有非常高的沉积效率，并且有很高的穿透上皮并到达间质部位和循环系统的倾向。因此，接触NP可能会造成心肺损伤的风险，但这种类型的研究需要一种基于系统的方法。到目前为止，缺乏合适的细胞-NP暴露系统阻碍了吸入性暴露于金属NPs的心肺毒性的研究。 我的研究计划的长期目标是通过创新的毒理学方法阐明NP毒性的细胞和分子机制，从而更好地了解空气中金属基NPs如何与生物系统相互作用。该计划有两个主要目标：i)发展体外毒性测试系统，以更确定地筛选、分级和预测NPs的毒性效应；ii)使用毒物基因组学方法识别和表征原因因素和NP毒性。在接下来的五年里，我的短期目标是评估吸入金属纳米颗粒的毒性，并通过提供更多关于其原因和机制的信息，优先在动物研究中更深入地研究纳米颗粒。我特别建议：1)阐明NPs促进肺部细菌感染的潜在原因和机制；2)评估NPs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：(1)HQP为一个新的科学分支(纳米毒理学)提供独特的培训机会；(2)关于NP毒性等级的宝贵信息，以及将NPs作为成本效益筛选的体内试验的优先次序；(3)了解NPs暴露产生生物反应的机制，因为这将使我们处于有利地位，制定设计安全的NPs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.