Toxicological Profiling of Engineered Nanomaterials (ENMs) in the MPS (RES)

MPS (RES) 中工程纳米材料 (ENM) 的毒理学分析

• 批准号: 9341321
• 负责人: Andre Elias Nel
• 金额: $ 41.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341321
• 关键词: 3-Dimensional; Acute; Address; Adoptive Transfer; Animals; Antigen-Presenting Cells; Antigens; Autophagocytosis; Biochemical; Biodistribution; Biological Preservation; Blood Circulation; Categories; Cell membrane; Cell physiology; Cells; Cellular Structures; Chronic; Coculture Techniques; Collaborations; Data; Decision Analysis; Decision Making; Dendritic Cells; Development; Disease; Engineering; Exposure to; Goals; Hazard Assessment; Hazardous Substances; Hepatocyte; Hepatotoxicity; Human; Image; Immune system; In Vitro; Inflammasome; Inflammation; Injectable; Injection of therapeutic agent; Injury; Intravenous; Knowledge; Kupffer Cells; Libraries; Link; Liver; Lung; Mediating; Methods; Mission; Modeling; Molecular; Mononuclear; Mus; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peptides; Phagocytes; Pharmaceutical Preparations; Physiological; Property; Public Health; Reporter Genes; Research; Research Personnel; Reticuloendothelial System; Risk; Risk Assessment; Safety; Shapes; Skin; Structure-Activity Relationship; Surface; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Toxicity Tests; Toxicology; Transgenic Animals; United States National Institutes of Health; Work; adverse outcome; antigen challenge; base; body system; combinatorial; design; disability; experience; hazard; immunotoxicity; in vivo; innovation; macrophage; nano; nanomaterials; nanoparticle; new technology; novel; predictive modeling; protective effect; response; screening

Project Summary There is a fundamental gap in understanding the impact of engineered nanomaterials (ENM) on the mononuclear phagocyte system (MPS), including Kupffer cells (KC) in the liver and antigen-presenting dendritic cells (DC) in the immune system. Our long-term goal is to develop a predictive 21st century toxicological platform for ENM safety assessment that is premised on cellular and organotypic cultures for high content screening, in which we will use adverse outcome pathways (AOPs) to derive structure-activity relationships (SARs) for toxicological profiling and decision analysis on consortium-provided ENMs. The overall objective is to use our mechanistic and high content screening approaches to perform hazard ranking, tiered risk assessment, and SAR analysis that link ENM physicochemical properties to AOPs in KC and DC, which is then used as the basis of in vivo predictions of the adverse impact on the liver and immune system. Our central hypothesis is that linkage of the ENM properties to molecular and pathophysiological alterations in the MPS will allow a mechanistic and high throughput approach for predicting the hazardous impact of ENMs on the MPS. The rationale of the proposed research is that the development of predictive and alternative testing platforms, including organotypic and cell co-culture models, will allow expedited risk assessment and categorization of broad ENM categories. Guided by our extensive experience for predictive toxicological modeling, we propose to explore the impact of the consortium-provided ENMs on the MPS in three specific aims: Aim 1: To use mechanistic, high content screening for hazard ranking and toxicological profiling of a diverse range of ENMs in KC and DC for SAR analysis and predictive toxicological profiling that can be used to plan studies in liver micro-tissues and animals. Aim 2: To use organotypic 3-D liver models, and limited in vivo toxicity assessment, imaging and biodistribution studies for toxicological profiling of a diverse range of related to toxicological injury pathways at the KC/hepatocyte interface and the liver of transgenic animals that express reporter genes (e.g., NF-κB). Aim 3: To use an antigen-specific (OVA peptide) dendritic and T-cell co-culture system and adoptive transfer in mice for toxicological and immunotoxicological profiling of a diverse range of ENMs, prior screened in Aim 1. Our approach is innovative, because of the substantive departure from the current status quo, where descriptive single agent toxicity testing will be replaced by rapid throughput, high content, and AOP-based predictive toxicological approaches for ENM effects on the MPS. The proposed research is significant because we will introduce mechanisms-based HTS approaches that can be used to link ENMs physicochemical properties to cellular and molecular response profiles for hazard profiling of intravenous injected ENMs. Not only will this provide a platform for expedited safety assessment of ENMs, but will also form the basis of extensive collaboration with the consortium, where predictive modeling can be used to study exposure systems such as the lung, GIT and the skin.

项目摘要 了解工程纳米材料（ENM）对 单核吞噬细胞系统（MPS），包括肝脏中的库普弗细胞（KC）和抗原呈递 免疫系统中的树突状细胞（DC）。我们的长期目标是发展21世纪的预测性 用于ENM安全评估的毒理学平台，该平台以高细胞和有机培养为前提 内容筛选，其中我们将使用不良结果途径（AOPS）来得出结构活动 关于财团提供的ENM的毒理学分析和决策分析的关系（SARS）。这 总体目标是使用我们的机械和高内容筛选方法来执行危险排名， 分层风险评估和SAR分析将ENM物理性质与KC和DC中的AOP联系起来， 然后将其用作对肝脏和免疫系统不利影响的体内预测的基础。 我们的中心假设是，ENM特性与分子和病理生理变化的联系 国会议员将允许一种机械和高通量方法来预测ENM的危险影响 在国会议员上。拟议研究的理由是预测和替代方案的发展 测试平台，包括有机和细胞共培养模型，将允许加快风险评估和 广泛的ENM类别的分类。以我们丰富的预测毒理学经验为指导 建模，我们建议在三个特定的特定方面探索财团提供的ENM对MPS的影响 目的：目的1：使用机械，高内容筛选的危害排名和毒理学分析 KC和DC中的各种ENM范围用于SAR分析和预测毒理学分析，可用于 在肝脏微型组织和动物中进行计划研究。目标2：使用有机3-D肝模型，并在体内限制 毒性评估，成像和生物分布研究，用于潜水员相关范围的毒理学分析 在KC/肝细胞界面和表达转基因动物的肝脏的毒理损伤途径 报告基因（例如NF-κB）。目标3：使用抗原特异性（OVA胡椒）树突状和T-Cell共培养 在潜水员范围的毒理学和免疫毒性分析的小鼠中的系统和适应性转移 ENM，事先在AIM 1中进行了筛选。我们的方法是创新的，因为 当前现状，其中描述性的单位毒性测试将被快速吞吐量取代 含量和基于AOP的ENM对MP的影响的预测毒理学方法。提议 研究很重要，因为我们将介绍可用于链接的基于机制的HTS方法 ENMS物理特性，具有细胞和分子响应曲线的危险分析 静脉注射ENM。这不仅会为ENM的加快安全评估提供一个平台，而且还可以 还将构成与财团进行广泛合作的基础，可以在其中使用预测性建模 研究暴露系统，例如肺，GIT和皮肤。