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小鼠中ENP的生物活性和生物反应。这项研究将使用定制设计的材料进行，这些材料含有超顺磁性氧化铁核， 荧光标记，并官能化以提供一系列净电荷。在目标1中，我们将使用一种新的磁性颗粒检测系统和荧光显微镜对ENPs进行定量和定位，以表征吸入暴露后官能化铁、铈和二氧化硅的生物学特性。生物动力学结果将在基于生理学的药代动力学模型中正式确定。在目标2中 我们假设网状内皮系统中的遗传缺陷（清道夫受体的缺失）将根据ENPs的大小和净电荷改变ENPs的组织/细胞生物学特性。我们还提出，在小鼠中ENPs的组织/细胞剂量和生物学活性将受到通过下呼吸道结构变化引起的肺功能扰动的扰动。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对生物组织水平的反应进行排名，促进了这种联系。该项目的创新之处在于其重点是可耐受性和临床重要终点。

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.