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

 描述（由申请人提供） 在职业和环境中，人类对工业相关工程纳米材料的接触正在增加。吸入是主要的进入途径。空气中的纳米颗粒（NP）到达肺的深肺泡区域，在那里它们遇到肺泡衬里液的生物分子。这种相互作用导致在NP表面上形成磷脂-蛋白质“冠”。在这种遭遇的第一步是低估和不好的特点，但在确定随后的命运和影响的NP是至关重要的。 研究人员的初步数据显示，不同化学成分的纳米颗粒在与肺衬里液的生物分子相互作用时会形成一种特征性的磷脂蛋白质冠。 他们还发现这些不同纳米颗粒的肺部反应和肺部清除率存在显着差异。随着纳米技术领域的迅速扩大，正在产生数百种具有不同物理化学性质的新型纳米颗粒。由于NP化学、电荷、大小或形状的每一个变化都构成了需要毒理学研究的潜在新材料，因此单独评价所有这些材料的毒性几乎是不可能的，而且成本过高。因此，开发用于预测纳米颗粒肺部清除率和毒性的高通量筛选试验是一个迫切的未满足的需求。这项全面的研究将确定和连接磷脂蛋白质冠状分布的particokinetics和毒理学终点。研究人员建议检查肺衬里液的六种主要蛋白质和六种磷脂对巨噬细胞等细胞摄取NP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NP穿过空气血液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，如尺寸，形状和表面功能化对电晕组合物的影响。 他们将创建一个磷脂蛋白质冠状分布数据库，将冠状分析与分子动力学模拟数据相结合。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综合电晕分析来预测纳米毒性的类似努力），并解决了一个重要的需求。这项变革性的研究利用磷脂-蛋白质冠状分析来创建一个高通量预测纳米毒性模型，该模型可以识别控制NP毒性的关键因素。拟议的研究将使系统的风险评估和分类的纳米材料的基础上，除了其电晕配置文件和其他参数用于分组纳米材料，如其大小，物理化学特征，生物持久性和急性毒性。此外，该研究将有助于预防纳米材料的不利影响及其在纳米技术中的使用。

 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.