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

基本信息

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
项目类别：
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

项目摘要

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颗粒（ENP）的理化组成和结构如何决定小鼠的ENP生物动力学和生物学反应。这项研究将使用含有超级顺磁铁氧化铁核心的定制设计材料进行荧光标签，功能化以提供一系列净电荷。在AIM 1中，我们将使用新型的磁性颗粒检测系统和荧光显微镜进行吸入后的生物动力学，以量化ENPS的定量和本地化。生物动力学结果将在基于生理的药代动力学模型中形式化。在目标2中我们假设在reficuloendopherial系统中的遗传缺陷（寻宝受体的丧失）将根据ENP的大小和净电荷来修饰ENP的组织/细胞生物动力学。我们还建议，小鼠中ENP的组织/细胞剂量和生物动力学将因下呼吸道的结构变化而受到肺功能的扰动。这些基因型和表型修饰对纳米颗粒生物因素的后果应通过炎症反应的变化反映。 AIM 3将将这些生物动力学和生化结果与肺炎链球菌对肺部感染的敏感性改变。项目＃2的结果将提供项目＃1的体外机械重点与项目＃3的风险评估重点之间的关键实验联系。通过使用高度平行的实验系统，测试材料，生物反应测定和统计方法来促进这种联系，以对跨生物组织的反应进行对反应进行排名。该项目的专注于临床和临床上重要的终点，因此具有创新性。