Lipoprotein Corona Fingerprints: Implications for Pulmonary Clearance and Toxicity of Engineered Nanoparticles

脂蛋白电晕指纹：对工程纳米粒子的肺部清除和毒性的影响

• 批准号: 10112752
• 负责人: Nagarjun Konduru Venkata
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112752
• 关键词: Address; Adverse effects; Affect; Albumins; Alveolar; Alveolar Macrophages; Antioxidants; Artificial nanoparticles; Barium Sulfate; Biological; Blood-Air Barrier; Bronchoalveolar Lavage Fluid; Carbon; Cell Line; Cells; Characteristics; Charge; Chemicals; Chemistry; Classification; Cultured Cells; Data; Databases; Dose; Electron energy loss spectroscopy; Encapsulated; Engineering; Epithelial; Epithelial Cells; Exhibits; Exposure to; Fingerprint; Formulation; Generations; Grain; Human; In Vitro; Incubated; Individual; Inductively Coupled Plasma Mass Spectrometry; Industrialization; Inflammatory; Inflammatory Response; Inhalation; Insufflation; Kinetics; Libraries; Lipoproteins; Liquid substance; Lung; Mass Spectrum Analysis; Measurement; Mediating; Mentors; Metabolic Clearance Rate; Metals; Modeling; Molecular; Nanotechnology; Nature; Occupational; Phagocytes; Phase; Phospholipid Interaction; Phospholipids; Powder dose form; Prevention; Property; Proteins; Proteomics; PubMed; Pulmonary Surfactant-Associated Protein A; Rattus; Reactive Oxygen Species; Reporter; Research; Research Personnel; Risk Assessment; Role; Route; Shapes; Silicates; Silicon Dioxide; Surface; System; Techniques; Testing; Tissues; Toxic effect; Toxicology; United States National Institutes of Health; Work; Zinc Oxide; acute toxicity; base; bioprocess; ceric oxide; cerium oxide nanoparticle; cytokine; experimental study; exposed human population; gel electrophoresis; high throughput screening; immunoregulation; in vivo; macrophage; metal oxide; molecular dynamics; nanomaterials; nanoparticle; nanotoxicity; novel; particle; predictive test; public health relevance; response; simulation; unilamellar vesicle; uptake

 DESCRIPTION (provided by applicant) Human exposures to industrially relevant engineered nanomaterials (ENMs) are increasing in occupational and environmental settings. Inhalation is a major route of entry. Airborne nanoparticles (NPs) reach the deep alveolar region of the lung where they encounter biomolecules of the alveolar lining fluid. The interaction results in the formation of a phospholipid-protein "corona" on the NP surface. The very first step in this encounter is underappreciated and poorly characterized, but is critical in determining subsequent fate and effects of NPs. The investigators preliminary data show that NPs of different chemical composition develop a characteristic phospholipid-protein corona while interacting with biomolecules of lung lining fluid. They also found the pulmonary responses and lung clearance profiles for these diverse NPs to be dramatically different. With the rapidly expanding field of nanotechnology, hundreds of novel NPs exhibiting diverse physicochemical properties are being generated. It would be practically impossible and prohibitively expensive to evaluate toxicity of all of them individually as every change in NP chemistry, charge, size, or shape constitutes a potentially new material requiring toxicological study. Therefore, there is an urgent unmet need for developing high-throughput screening assays for predicting pulmonary clearance and toxicity of NPs. This comprehensive study will identify and connect phospholipid-protein corona profiles to particokinetic and toxicological endpoints. The investigators propose to examine the independent and collective effects of the six major proteins and six phospholipids of lung lining fluid on the uptake of NPs by cells such as macrophages and their subsequent responses. They will also evaluate the role of the phospholipid-protein corona in modulating translocation of NPs across the air blood barrier. Additionally, the investigators propose molecular dynamic simulation studies for understanding the nature of NP-biomolecular interactions in alveoli. They will test the effects of varying physicochemical properties such as size, shape and surface functionalization on the corona composition. They will create a phospholipid-protein corona profile database library that integrates corona analyses with molecular dynamic simulation data. While the project builds on extant work in the field, it is unique (a search of NIH Reporter and PubMed does not reveal any similar efforts that use comprehensive corona profiling to predict nanotoxicity) and addresses an important need. This transformative study takes advantage of phospholipid-protein corona profiling to create a high-throughput predictive nanotoxicity model that identifies critical factors controlling NP toxicity. The proposed research will enable systematic risk assessment and classification of nanomaterials based on their corona profiles in addition to other parameters used to group nanomaterials such as their size, physicochemical features, biopersistence and acute toxicity. Further, the study will enable in prevention of the adverse effects of nanomaterials and their use in nanotechnology.

 描述（由申请人提供） 人类对工业相关工程纳米材料（ENM）的暴露量正在增加占领和环境环境。吸入是主要入境途径。空气中的纳米颗粒（NP）到达肺部的深肺泡区域，在那里它们遇到肺泡衬里的生物分子。这种相互作用导致在NP表面形成磷脂蛋白“电晕”。这次遭遇的第一步是不足的且特征不佳，但对于确定随后的命运和NP的影响至关重要。研究者的初步数据表明，不同化学成分的NP与肺衬里液体的生物分子相互作用时会形成特征性的磷脂蛋白电晕。他们还发现这些潜水员NP的肺反应和肺清除曲线在动态上不同。随着纳米技术的快速扩展领域，正在产生数百种具有潜水员物理特性的新型NP。由于NP化学，充电，大小或形状的每一次变化构成了需要毒理学研究的潜在材料，因此几乎不可能评估所有这些毒性。因此，迫切需要开发高通量筛查测定法，以预测NP的肺部清除和毒性。这项全面的研究将识别并将磷脂蛋白电蛋白电晕谱与特定动力学和毒理学终点联系起来。研究人员建议检查六种主要蛋白质和六种肺衬里的六磷脂的独立和集体作用对巨噬细胞（例如巨噬细胞及其随后的反应）摄取NP的摄取。他们还将评估磷脂蛋白毒素电晕在调节空气屏障中NP的易位方面的作用。此外，研究人员提出了分子动力学仿真研究，以理解肺泡中NP - 双分子相互作用的性质。他们将测试各种物理特性的影响，例如大小，形状和表面功能化对电晕组成的影响。他们将创建一个磷脂蛋白电晕轮廓数据库库，该数据库与分子动态模拟数据集成了电晕分析。虽然该项目建立在现场现有工作的基础上，但它是唯一的（对NIH记者和PubMed的搜索并未揭示出任何使用全面的电晕分析来预测纳米毒性的类似努力），并满足了重要的需求。这项变革性研究利用了磷脂蛋白电晕分析，创建了一个高通量预测性纳米毒性模型，该模型鉴定了控制NP毒性的关键因素。拟议的研究还将根据其Corona概况对纳米材料进行系统的风险评估和分类，除了用于将纳米材料的其他参数分组，例如其大小，物理特征，生物抗性和急性毒性。此外，该研究将有助于预防纳米材料的不良影响及其在纳米技术中的使用。