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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

基本信息

批准号：
9186735
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
项目类别：
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/9186735
关键词：
3-Dimensional Acute Address Adoptive Transfer Animals Antigens Autophagocytosis Biochemical Biocompatible Coated Materials 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 Inflammation 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 Transgenic Animals Work adverse outcome animal tissue 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

项目摘要

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.

项目总结