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

基本信息

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
项目类别：
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

项目摘要

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）在职业和环境环境中，人类对工业相关工程纳米材料 (ENM) 的接触不断增加。吸入是空气中的纳米粒子 (NP) 进入肺泡深处并与肺泡内层液体的生物分子相互作用的主要途径。导致在 NP 表面形成磷脂蛋白“冠”。这种遭遇的第一步并未得到充分重视，也没有得到很好的表征，但对于决定后续的命运至关重要。研究人员的初步数据表明，不同化学物质的纳米粒子在与肺内壁液体的生物分子相互作用时会形成特征性的磷脂蛋白冠，他们还发现这些不同的纳米粒子的肺部反应和肺清除率显着不同。随着纳米技术领域的迅速扩展，数百种具有不同物理化学性质的新型纳米粒子正在产生，因为纳米粒子化学、电荷、化学性质的每一次变化，单独评估所有这些纳米粒子的毒性实际上是不可能的，而且成本高昂。因此，迫切需要开发高通量筛选方法来预测 NP 的肺部清除率和毒性。这项综合研究将识别磷脂-蛋白冠谱并将其与它们联系起来。研究人员建议检查肺衬液中六种主要蛋白质和六种磷脂对巨噬细胞等细胞摄取纳米粒子及其随后反应的独立和集体影响。他们还将评估磷脂-蛋白质冠在调节纳米粒子穿过气血屏障的易位中的作用，此外，研究人员提出了分子动力学模拟研究，以了解肺泡中纳米粒子-生物分子相互作用的性质。他们将创建一个磷脂-蛋白质电晕谱数据库，该数据库将电晕分析与分子动态模拟数据结合起来。与该领域的现有工作相比，它是独一无二的（对 NIH Reporter 和 PubMed 的搜索没有发现任何使用综合电晕分析来预测纳米毒性的类似努力），并且这项变革性研究利用磷脂-蛋白质电晕分析来解决一个重要需求。创建一个高通量预测纳米毒性模型，该模型可识别控制纳米颗粒毒性的关键因素。除了用于对纳米材料进行分组的其他参数外，拟议的研究还将根据其电晕分布对纳米材料进行系统的风险评估和分类。此外，该研究还将有助于预防纳米材料及其在纳米技术中的应用的不利影响。