Nano-Bio Interactions at the Surface of Pulmonary Surfactant Films

主要研究者：Zuo，Yi #1604119纳米技术的快速发展和纳米消费品的广泛普及使人们越来越关注纳米颗粒（NP）对环境、健康和安全（EHS）的潜在不利影响，纳米颗粒的特征尺寸小于100 nm。大多数NP是轻质的和可呼吸的。一旦吸入，NP可以渗透到肺部并干扰呼吸功能。肺的整个表面衬有脂质-蛋白质肺表面活性剂（PS）膜，其起到宿主防御和表面张力降低的重要生理功能。因此，吸入的NP和PS膜之间的相互作用代表了肺中的初始纳米生物现象。这种相互作用决定了吸入的NP的命运及其潜在的治疗或毒理学作用。本提案将使用PI实验室开发的新实验和计算技术研究NP-PS相互作用的详细机制。这些技术允许高保真模拟空气污染情景，其中NP被吸入并沉积在PS膜的表面。使用这些模型系统，将彻底评估纳米粒子和纳米产品（如含纳米粒子的喷雾剂和油漆）的潜在环境危害。PI将特别关注研究可吸入NP对婴儿和儿童的潜在风险，这些婴儿和儿童脆弱的呼吸系统使其比成人更容易受到NP暴露的影响。拟议的研究将有助于提供一个有用的指标，以规范和监督纳米技术的商业应用，以实现更安全和可持续的发展。本课题的研究目标是研究气载工程纳米颗粒与天然肺表面活性物质相互作用的详细生物化学机制。这项研究是非常新颖的，由于以下两个主要观点。首先，NP-PS相互作用将使用多尺度体外模拟和计算机模拟相结合的方法进行研究。体外研究依赖于使用PI实验室最近开发的新实验方法的生物物理模拟。使用该体外模型，将在生理相关呼吸条件下，使用完全受控的NP气溶胶剂量测定法模拟PS膜处的纳米生物相互作用。计算机模拟研究依赖于高保真的分子动力学模拟，其允许探测NP易位穿过PS膜的详细分子机制。其次，PI将对与肺液接触的NP结合的生物分子冠进行首次全面研究，即，所谓的PS生物分子冠。通过相关的高精度质谱和分子动力学模拟，该项目将以前所未有的细节揭示PS生物分子冠的生物化学组成和生物物理构象。这项研究预计将显着推进目前的理解呼吸系统中的纳米生物相互作用，并提供新的洞察到EHS的影响纳米technology.The更广泛的影响，这一建议是丰富和多样的。本提案中开发的体外和计算机模拟是探索纳米技术对EHS影响的具有成本效益的手段。拟议的研究将补充目前从细胞培养和动物模型中获得的纳米毒理学知识。本研究揭示的生物药物化学机制对于设计基于NP的肺部药物递送以及更好地理解与空气污染和颗粒损伤相关的呼吸系统疾病的病理生理学具有明确的变革价值。PI与当地医疗保健提供者合作，开展活动，提高公众对婴儿和儿童吸入性NP潜在风险的认识。鉴于夏威夷大学独特的地理位置，PI致力于促进夏威夷土著人、太平洋岛民以及来自其他代表性不足群体和低收入家庭的学生的参与。PI还将开发具有跨学科内容的本科生和研究生工程课程，并帮助加强研究和教育的基础设施。

PI: Zuo, Yi#1604119The rapid development of nanotechnology and a widespread proliferation of nano-enabled consumer products post an increasing concern of the potential adverse environment, health, and safety (EHS) impacts of nanoparticles (NPs), which feature a characteristic size less than 100 nm. Most NPs are lightweight and respirable. Once inhaled, NPs can penetrate into the lungs and interfere with the respiratory function. The entire surface of the lungs is lined with a lipid-protein pulmonary surfactant (PS) film which serves an important physiological function of host defense and surface tension reduction. Interactions between inhaled NPs and the PS film hence represent the initial nano-bio phenomena in the lungs. Such interactions determine the fate of the inhaled NPs and their potential therapeutic or toxicological effects. This proposal will investigate the detailed mechanism of NP-PS interactions using novel experimental and computational techniques developed in the PI's laboratory. These techniques allow high-fidelity simulations of air pollution scenarios in which NPs are inhaled and deposited at the surface of the PS film. Using these model systems, potential environmental hazards of NPs and nano-enabled products, such as NP-containing sprays and paints, will be thoroughly evaluated. The PI will specifically focus on studying the potential risk of respirable NPs for infants and children whose fragile respiratory system makes them more vulnerable to NP exposure than adults. The proposed study will help provide a useful metric for regulating and overseeing commercial applications of nanotechnology towards a safer and sustainable development. The research goal of this proposal is to study the detailed biophysicochemical mechanisms by which airborne engineered nanoparticles (NPs) interact with natural pulmonary surfactant (PS). This research is highly novel due to the following two main perspectives. First, NP-PS interactions will be studied using a combined approach of multiscale in vitro and in silico simulations. The in vitro study relies on biophysical simulations using a novel experimental methodology recently developed in the PI's laboratory. With this in vitro model, nano-bio interactions at the PS film will be mimicked with fully controlled NP aerosol dosimetry and under physiologically relevant respiratory conditions. The in silico study relies on high-fidelity molecular dynamics simulations which allow probing the detailed molecular mechanism of NP translocation across the PS film. Second, the PI will carry out the first comprehensive study of the biomolecular corona bound to NPs in contact with lung fluids, i.e., the so-called PS biomolecular corona. With correlated high-precision mass spectrometry and molecular dynamics simulations, the proposed project will reveal the biochemical composition and biophysical conformation of the PS biomolecular corona with unprecedented details. This research is expected to significantly advance current understanding of nano-bio interactions in the respiratory system and to provide novel insight into the EHS impacts of nanotechnology.The broader impacts of this proposal are rich and multifarious. In vitro and in silico simulations developed in this proposal are cost-effective means of exploring the EHS impacts of nanotechnology. The proposed study will complement the current nanotoxicological knowledge obtained from cell culture and animal-models. The biophysicochemical mechanism revealed by this study has clear transformative values for designing NP-based pulmonary drug delivery and for better understanding the pathophysiology of respiratory diseases related to air pollution and particle insult. In collaboration with local healthcare providers, the PI is engaged in activities of increasing the public awareness of the potential risk of respirable NPs for infants and children. Given the unique location of the University of Hawaii, the PI is dedicated to promoting participation of Native Hawaiians, Pacific Islanders, and students from other underrepresented groups and low-income families. The PI will also develop undergraduate and graduate engineering curricula with interdisciplinary components, and help enhance the infrastructure for research and education.