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

项目2的组织目标是了解工程纳米颗粒(ENPs)的物理化学组成和结构如何决定ENP在小鼠体内的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， 荧光标签，并进行了功能化，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对ENPs进行定量和定位，以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。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。在AIM 2 我们假设，内皮系统中的遗传缺陷(清道夫受体的丢失)将根据ENPs的大小和净电荷改变其组织/细胞生物动力学。我们还提出，ENPs在小鼠体内的组织/细胞剂量和生物动力学将受到肺功能扰动的影响，这种扰动是通过下呼吸道的结构变化来实现的。这些基因和表型改变对纳米生物动学的影响应该反映在炎症反应的变化上。目的3将这些生物动力学和生化结果与肺炎链球菌肺部感染易感性的改变联系起来。 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。这种联系是通过使用高度平行的实验系统、测试材料、生物反应分析和统计方法来对生物组织各级的反应进行排名而促进的。该项目是创新的，因为它的重点是易感和临床重要的终点。

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.