Project 2: Role of ENP Physicochemical Properties on Biokinetics and Response in

项目 2：ENP 理化性质对生物动力学和反应的作用

• 批准号: 8067695
• 负责人: Joel G Pounds
• 金额: $ 26.05万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067695
• 关键词: Adverse effects; Affect; Age; Air; Air Pollution; Alveolar Macrophages; Artificial nanoparticles; Attention; Bacteria; Biochemical; Biocompatible Materials; Biological; Biological Assay; Breathing; Cell physiology; Cells; Cerium; Charge; Chemistry; Communities; Complex; Custom; Data; Defect; Detection; Disease; Dose; Drug Kinetics; Dust; Elastases; Engineering; Epidemiologic Studies; Exposure to; Fluorescence Microscopy; Gender; Genes; Genetic; Genetic Predisposition to Disease; Genetically Engineered Mouse; Genotype; Goals; Hazard Assessment; Health; Hereditary Disease; Hospitalization; Impairment; In Vitro; Individual; Infection; Inflammatory Response; Inhalation Exposure; Intranasal Administration; Iron; Kinetics; Knock-out; Knockout Mice; Knowledge; Label; Link; Lower respiratory tract structure; Lung; Lung diseases; Magnetism; Materials Testing; Measures; Mediating; Membrane; Microscopy; Modification; Molecular; Mus; Mutation; Organism; Outcome; Oxides; Particulate; Phagocytosis; Phenotype; Pneumonia; Populations at Risk; Predisposition; Property; Protein Analysis; Pulmonary Emphysema; Research; Respiratory System; Respiratory tract structure; Reticuloendothelial System; Risk; Risk Assessment; Rodent; Role; Route; Science; Series; Silicon Dioxide; Streptococcus pneumoniae; Structure; Surface; System; Testing; Tissues; Toxic Environmental Substances; Toxic effect; Toxicokinetics; base; ceric oxide; clinically relevant; cytotoxicity; design; exposed human population; in vivo; inflammatory marker; innovation; iron oxide; killings; macrophage; macrophage scavenger receptors; metal oxide; nanomaterials; nanoparticle; novel; particle; pathogen; pharmacokinetic model; pulmonary function; receptor; research study; response; scavenger receptor; sound; toxicant; uptake

The organizing Goal of Project 2 is to understand how the physicochemical composition and structure of engineered nanoparticles (ENPs) dictate ENP biokinetics and biological response in mice. This research will be conducted using custom-designed materials that contain a super paramagnetic iron oxide core, fluorescent labels, and functionalized to provide a range of net charges. In Aim 1 we will characterize the biokinetics of funcfionalized iron, cerium, and silica oxides following inhalation exposure using a novel Magnetic Particle Detection system and fluorescence microscopy for quantitation and localizafion of the ENPs. The biokinetic results will be formalized in a Physiologically-Based Pharmacokinetic model. In Aim 2 we hypothesize that genetic defects in the reficuloendothelial system, (loss of scavenger receptors) will modify the tissue/cellular biokinetics of ENPs according to their size and net charge. We also propose that the tissue/cell dose and biokinetics of ENPs in mice will be perturbed by perturbafion of pulmonary function via structural changes in the lower respiratory tract. The consequences of these genotype and phenotype modifications on nanoparticle biokinefics should be reflected by changes in the inflammatory response. Aim 3 will relate these biokinetic and biochemical results to altered susceptibility to pulmonary infecfion by Streptococcus pneumoniae. The results from Project #2 will provide the critical experimental link between the in vitro mechanistic focus of Project #1 and the risk assessment focus of Project #3. This link is facilitated by use of highly parallel experimental systems, test materials, biological response assays, and statistical approaches to rank response across levels of biological organization. This Project is innovative for its focus on susceptibillty and clinically important endpoints.

项目 2 的组织目标是了解工程纳米粒子 (ENP) 的物理化学组成和结构如何决定小鼠体内的 ENP 生物动力学和生物反应。这项研究将使用包含超顺磁性氧化铁核心的定制设计材料进行， 荧光标记，并进行功能化以提供一系列净电荷。在目标 1 中，我们将使用新型磁粒子检测系统和荧光显微镜来表征吸入暴露后功能化铁、铈和二氧化硅氧化物的生物动力学，以对 ENP 进行定量和定位。生物动力学结果将在基于生理学的药代动力学模型中形式化。目标 2 我们假设网状内皮系统的遗传缺陷（清道夫受体的丧失）将根据 ENP 的大小和净电荷改变其组织/细胞生物动力学。我们还提出，小鼠中 ENP 的组织/细胞剂量和生物动力学将受到下呼吸道结构变化对肺功能的干扰。这些基因型和表型修饰对纳米颗粒生物动力学的影响应该通过炎症反应的变化来反映。目标 3 将这些生物动力学和生化结果与肺炎链球菌肺部感染的易感性改变联系起来。 项目#2 的结果将提供项目#1 的体外机制重点和项目#3 的风险评估重点之间的关键实验联系。通过使用高度并行的实验系统、测试材料、生物反应测定和对生物组织各个级别的反应进行排名的统计方法，可以促进这种联系。该项目的创新之处在于其重点关注敏感性和临床重要终点。