Project 1: Mechanisms of Nanomaterial-Cell Interactions

项目1：纳米材料-细胞相互作用机制

基本信息

批准号：
8274447
负责人：
Brian Thrall
金额：
$ 53.3万
依托单位：
BATTELLE PACIFIC NORTHWEST LABORATORIES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8274447
关键词：
Active Biological Transport Affect Air Pollution Alveolar Macrophages Artificial nanoparticles Attention Biodistribution Bioinformatics Biological Biological Assay Biometry Breathing Cell Communication Cell Wall Cell physiology Cells Charge Chemistry Clathrin Collaborations Data Dependence Detection Development Dose Environment Event Experimental Designs Exposure to Flow Cytometry Genes Genetic Genomics Goals Hospitalization Human Immune In Vitro Infection Inflammatory Kupffer Cells Ligands Liquid substance Lung Lysosomes Magnetism Measurement Measures Mediating Microscopy Modeling Molecular Mus National Institute of Environmental Health Sciences Natural Immunity Organelles Oxides Particulate Pathway interactions Pattern recognition receptor Phagocytosis Physiological Physiology Play Polystyrenes Predisposition Property Quantitative Structure-Activity Relationship Regulatory Pathway Research Research Personnel Resources Risk Risk Assessment Role SR-A proteins Science Serum Proteins Signal Transduction Silicon Dioxide Solubility Streptococcus pneumoniae Structure Surface System Testing base biodosimetry cell type cellular imaging ceric oxide clinically relevant design dosimetry exposed human population feeding hazard in vitro Model in vivo innate immune function intercellular communication iron oxide killings macrophage macrophage scavenger receptors member model development nanomaterials oxidized lipid particle pathogen receptor receptor expression receptor function response scavenger receptor trafficking uptake

项目摘要

The overarching goal of Project 1 is to understand how the physicochemical composition and structure of engineered nanoparticles (ENPs) dictate their biological interaction with cells to ultimately affect signaling and physiology. We hypothesize that scavenger receptor pathways plays a prominent role in determining the intracellular dose of ENPs in macrophages and biodistribution of ENPs in vivo. We further hypothesize that ENPs that "hijack' scavenger receptor uptake pathways may compromise macrophages ability to phagocytose and/or kill common bacterial lung pathogens. To test these hypotheses, microscopy, flow cytometry, and magnetic particle detection (MPD) will be used to quantitatively determine how varying the size, surface chemistry, charge and agglomeration state of ENPs (cerium oxides, silica oxides, iron oxides) affects their rate of uptake and trafficking pathways in macrophages derived from wildtype mice and mice deficient in class A scavenger receptors (Aim1). We will determine how the physicochemical properties of the ENPs affect stability of lysosomes, and their ability to activation inflammasome signaling (Aim 2). In vitro macrophage infection studies will be conducted to determine whether ENPs internalized by scavenger receptor pathways compromise the macrophages ability to recognize, phagocytosis and kill pathogens, using streptococcus pneumoniae as a model human lung pathogen (Aim 3). Finally, we will apply genomic microarray and bioinformatic analyses to identify gene regulatory pathways modulated by scavenger receptors and expore mechanisms by which ENPs may affect innate immune functions of macrophages (Aim 4). The dose-response studies in this project are designed to feed data directly for quantitative structure activity relationship analysis and development of dosimetry and risk models in Project 3. The results will also provide a molecular basis for experimental design and interpretation of parallel in vivo biodistribution and pathogen infection studies to be conducted in Project 2. We envision the proposed approach can provide quantitative data for hazard and risk analysis that is focused on clinically relevant measures of macrophage function that are potentially impacted by low level exposures to ENPs.

项目1的总体目标是了解工程纳米颗粒（ENP）的物理化学组成和结构如何决定其与细胞的生物学相互作用，以最终影响信号传导和生理。我们假设清道夫受体途径在确定中起着重要的作用巨噬细胞中ENP的细胞内剂量和体内ENP的生物分布。我们进一步假设，ENPS“劫持的清道受体摄取途径可能会损害巨噬细胞的能力和/或杀死常见的细菌性肺病原体。测试这些假设，显微镜，流式细胞术和磁性粒子检测（MPD）的范围，将用于量化量的量化，以确定量的量化，并确定量的范围，并确定范围的量，并表面启动（表面量），并且表面的范围（MPD）的大小（凝聚）（cot）的大小（均匀范围）（量），并构成了尺寸（凝聚）（均匀范围）（范围（MPD），并且范围（MPD）的大小（iNST），并且是范围的（MPD）。氧化物，二氧化硅，铁氧化物）会影响源自野生型小鼠的巨噬细胞的摄取速率和运输途径，而在A级清除剂受体中缺乏的小鼠（AIM1）。 ENP会影响溶酶体的稳定性及其激活炎性体信号传导的能力（AIM 2）。将进行体外巨噬细胞感染研究，以确定通过清道夫受体途径内部化的ENP是否会损害巨噬细胞识别，吞噬和杀死病原体的巨噬细胞的能力肺炎链球菌作为模型人肺病原体（AIM 3）。最后，我们将采用基因组微阵列和生物信息学分析来识别由清道夫受体调节的基因调节途径，并实现ENP可能影响巨噬细胞的先天免疫功能的机制（AIM 4）。该项目中的剂量反应研究旨在直接馈送数据，以用于定量结构活动关系分析和项目3中的剂量测定和风险模型的开发。结果还将为实验设计和平行的体内生物分布和病原体感染研究提供的实验设计和解释提供分子基础。危害和风险分析的定量数据集中在临床相关的巨噬细胞功能的指标上，这些测量可能受到向ENPS低水平暴露的影响。