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: 9329451
• 负责人: Nagarjun Konduru Venkata
• 金额: $ 10.18万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-10-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329451
• 关键词: Address; Adverse effects; Affect; Albumins; Alveolar; Alveolar Macrophages; Antioxidants; Artificial nanoparticles; Barium Sulfate; Biological; Biological Assay; Blood-Air Barrier; Breathing; Bronchoalveolar Lavage Fluid; Carbon; Cell Line; Cells; Cereals; 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; Human; In Vitro; Incubated; Individual; Inductively Coupled Plasma Mass Spectrometry; Industrialization; Inflammatory; Inflammatory Response; 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; 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) 在职业和环境环境中，人类对工业相关的工程纳米材料(ENM)的暴露正在增加。吸入是进入的主要途径。空气中的纳米颗粒(NPs)到达肺的深层肺泡区域，在那里它们遇到了肺泡衬里液体的生物分子。这种相互作用导致在NP表面形成磷脂-蛋白质“日冕”。这一遭遇的第一步没有得到充分认识，特点也不佳，但对决定核动力源随后的命运和影响至关重要。研究人员的初步数据显示，不同化学成分的NPs在与肺衬里液体的生物分子相互作用时，会形成一种特征的磷脂-蛋白质冠状结构。他们还发现，这些不同的NPs的肺反应和肺清除情况截然不同。随着纳米技术领域的迅速扩展，数以百计的具有不同物理化学性质的新型纳米粒子正在被产生。单独评估所有这些物质的毒性几乎是不可能的，而且费用高得令人望而却步，因为NP化学、电荷、尺寸或形状的每一次变化都构成了一种潜在的新材料，需要进行毒理学研究。因此，迫切需要开发高通量筛查方法来预测NPs的肺清除和毒性。这项全面的研究将确定磷脂-蛋白质冠状图谱，并将其与部分动力学和毒理学终点联系起来。研究人员建议研究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NPS及其后续反应的独立和集体影响。他们还将评估磷脂蛋白日冕在调节NPs跨越空气-血液屏障的转移中的作用。此外，研究人员建议进行分子动力学模拟研究，以了解肺泡内NP-生物分子相互作用的性质。他们将测试不同的物理化学性质，如大小、形状和表面功能化对电晕成分的影响。他们将创建一个磷脂-蛋白质日冕轮廓数据库，将日冕分析与分子动态模拟数据相结合。虽然该项目建立在该领域现有工作的基础上，但它是独一无二的(NIH Reporter和PubMed的搜索没有发现任何使用全面电晕剖析来预测纳米毒性的类似努力)，并满足了一个重要的需求。这项变革性的研究利用磷脂-蛋白质冠状图谱创建了一个高通量预测纳米毒性模型，该模型确定了控制NP毒性的关键因素。拟议的研究将能够根据纳米材料的电晕分布以及用于对纳米材料进行分组的其他参数，如其尺寸、物理化学特征、生物持久性和急性毒性，对纳米材料进行系统的风险评估和分类。此外，这项研究将有助于防止纳米材料的不利影响及其在纳米技术中的使用。