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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=U01ES030672&format=word)
Principal Investigator: Jordt, Sven-Eric | |
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Institute Receiving Award | Duke University |
Location | Durham, NC |
Grant Number | U01ES030672 |
Funding Organization | National Institute of Environmental Health Sciences |
Award Funding Period | 01 Sep 2019 to 31 Aug 2024 |
DESCRIPTION (provided by applicant): | Summary Chlorine gas has been used as a terrorist weapon, in warfare and has injured many Americans in transportation or industrial accidents. Despite its devastating effects, no mechanism-based treatment has been developed. In this application, we hypothesize that targeting the TRPA1 ion channel post-exposure will ameliorate the acute pulmonary, cardiovascular and neurological effects of chlorine, leading to decreased morbidity and improved recovery. TRPA1 is a chemical irritant receptor eliciting pain, edema, vasodilation, cardiac arrhythmia, inflammation and leukocyte infiltration. Our preliminary studies in mice show that TRPA1 inhibitors, when administered post-chlorine exposure, prevent the chlorine-induced decline of blood oxygenation, improve pulmonary function and mitigate inflammation. Here, we propose to test the efficacy of a 3rd generation TRPA1 inhibitor, found to block mouse, human and porcine TRPA1, in mouse and pig models of chlorine inhalation injury, with the goal to develop this compound as a future human countermeasure. The following aims are proposed: Aim 1: Screen potential therapeutic effects of a 3rd generation TRPA1 inhibitor in mouse models of Cl2 gas inhalation injury. Aim 2: Determine the pharmacokinetic and toxicological properties of TRPA1 inhibitor in pigs. Aim 3: Test the TRPA1 inhibitor in a pig model of chlorine gas inhalation injury |
Science Code(s)/Area of Science(s) |
Primary: 37 - Counter-Terrorism Secondary: 03 - Carcinogenesis/Cell Transformation |
Publications | See publications associated with this Grant. |
Program Officer | Srikanth Nadadur |