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

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $417,999

## Abstract

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 E...

## Key facts

- **NIH application ID:** 9995478
- **Project number:** 5U01ES027237-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Andre Elias Nel
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,999
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995478

## Citation

> US National Institutes of Health, RePORTER application 9995478, Toxicological Profiling of Engineered Nanomaterials (ENMs) in the MPS (RES) (5U01ES027237-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9995478. Licensed CC0.

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