# COUNTERACT Supplement--ASPIRE: Air Pollution: Strategies for Personalized Intervention to Reduce Exposure

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $124,998

## Abstract

ABSTRACT
Chlorine is a reactive gas that is a continuing chemical threat given the large amounts produced and used for
industrial application from both intentional and accidental release. The current administrative supplement to the
parent application is directed towards development of next generation therapeutics that can significantly reduce
mortality and morbidity in the event of release of this chemical threat. The studies published by our group in
from our parent grant have collectively paved the way for the concept that PM2.5 exposure results in systemic
inflammation (including neuronal inflammation) through TLR4 and oxidative stress pathways. Recently we have
demonstrated that the Nrf2-Keap2 system could represent a key pathway through which barrier function may be
maintained. Activation of Nrf2 may represent a therapeutic modality to abrogate barrier dysfunction and
attenuate chlorine injury. In this supplemental application we will test 2 aims that besides providing mechanistic
insights into cardiopulmonary injury with chlorine exposure will also test 2 strategies, TLR4 inhibition and Nrf2
activation in mitigating systemic inflammation in response to chlorine exposure. In Aim 1 we will examine the
effect of different doses of chlorine exposure on generation of TLR4 activators such as oxidized phospholipids in
the lung surfactant fluid and the impact of these on lung and systemic inflammation in wildtype, TLR4-/- and
Keap1-/-mice. We will investigate the impact of intranasal and systemic delivery of TLR4 inhibitors in protecting
against chlorine injury. In Aim 2 we will test the concept that blood brain barrier permeability with chlorine is an
important component of systemic toxicity and will test the impact of several novel small molecular Nrf2 activators
in reducing CNS and lung inflammation. To achieve these objectives and in order to extend the findings from the
original study (based on our preliminary studies) we request a specific supplement that will enable us to test
these concepts. We believe that this supplemental award is highly responsive to the special request for
supplements to the NIH Countermeasures Against Chemical Threats (CounterACT) program.

## Key facts

- **NIH application ID:** 10218398
- **Project number:** 3R01ES019616-09S1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Robert Daniel Brook
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $124,998
- **Award type:** 3
- **Project period:** 2011-02-04 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218398

## Citation

> US National Institutes of Health, RePORTER application 10218398, COUNTERACT Supplement--ASPIRE: Air Pollution: Strategies for Personalized Intervention to Reduce Exposure (3R01ES019616-09S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10218398. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*