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.

项目概要 在理解工程纳米材料 (ENM) 对环境的影响方面存在着根本性的差距。 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一个可预测的 21 世纪 用于 ENM 安全评估的毒理学平台，以细胞和器官型培养物为前提，用于高 内容筛选，其中我们将使用不良结果途径（AOP）来推导结构-活性 对联盟提供的 ENM 进行毒理学分析和决策分析的关系 (SAR)。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， 将 ENM 理化特性与 KC 和 DC 中的 AOP 联系起来的分层风险评估和 SAR 分析， 然后将其用作体内预测对肝脏和免疫系统不利影响的基础。 我们的中心假设是 ENM 特性与分子和病理生理学改变之间的联系 MPS 将允许采用机械和高通量方法来预测 ENM 的危险影响 在MPS上。拟议研究的基本原理是预测性和替代性的发展 测试平台，包括器官型和细胞共培养模型，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 建模时，我们建议在三个具体方面探讨联盟提供的 ENM 对 MPS 的影响 目标： 目标 1：使用机械的、高内涵的筛选方法对某种物质进行危害排名和毒理学分析。 KC 和 DC 中的各种 ENM，用于 SAR 分析和预测毒理学分析，可用于 计划对肝脏微组织和动物进行研究。目标 2：使用器官型 3-D 肝脏模型，并仅限于体内 毒性评估、成像和生物分布研究，用于各种相关物质的毒理学分析 表达KC/肝细胞界面和转基因动物肝脏的毒理学损伤途径 报告基因（例如 NF-κB）。目标 3：使用抗原特异性（OVA 肽）树突状细胞和 T 细胞共培养物 系统和小鼠过继转移，用于多种不同物质的毒理学和免疫毒理学分析 ENM，在目标 1 中预先筛选。我们的方法是创新的，因为与 目前的现状是，描述性的单一药物毒性测试将被快速通量、高通量的测试所取代。 内容，以及基于 AOP 的 ENM 对 MPS 影响的预测毒理学方法。拟议的 研究意义重大，因为我们将引入基于机制的 HTS 方法，可用于链接 ENM 的物理化学特性对细胞和分子响应曲线的危害分析 静脉注射ENM。这不仅将为 ENM 的快速安全评估提供一个平台，而且 还将构成与联盟广泛合作的基础，其中可以使用预测模型 研究肺部、胃肠道和皮肤等暴露系统。