Advanced TRPA1 Inhibitor for the Treatment of Chlorine Inhalation Injury

用于治疗氯吸入损伤的先进 TRPA1 抑制剂

基本信息

批准号：
10002221
负责人：
Satyanarayana Achanta
金额：
$ 76.98万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10002221
关键词：
Acrolein Acute Acute Lung Injury Airway Resistance American Animal Model Antidotes Arrhythmia Blood Blood specimen Bronchiolitis Obliterans Cardiovascular system Cell Count Cell Culture Techniques Chemical Weapons Chemicals Chlorine Clinical Trials Conflict (Psychology)Development Dose Drug Kinetics Edema Family suidae Frequencies Future Gases Generations Goals Histopathology Human In Vitro Industrial Accidents Infiltration Inflammation Inhalation Injury Intramuscular Investigational Therapies Ion Channel Irritants Leukocytes Lung Lung Inflammation Measures Modeling Morbidity - disease rate Mus Nervous system structure Neurologic Effect Oral Organ Oxygen Pain Partial Pressure Physiological Plasma Preparation Process Property Proteins Protocols documentation Recovery Respiratory System Riots Rodent Route Skin injury Supine Position Terrorism Testing Therapeutic Effect Therapeutic Studies Time Tissues Toxicology Transportation Treatment Efficacy United States Vasodilation Ventilator Vesicants Weight White Blood Cell Count procedure World War I animal rule appropriate dose base chlorine gas cytokine effective therapy efficacy testing improved in vivo indexing inhibitor/antagonist injured liquid chromatography mass spectrometry lung injury medical countermeasure methacholine mortality mouse model nerve supply pressure prevent primary endpoint pulmonary function receptor respiratory response sensor severe injury standard of care symptom treatment therapeutic evaluation weapons

项目摘要

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

概括氯气被用作战争中的恐怖武器，并伤害了许多美国人运输或工业事故。尽管有毁灭性的影响，但没有基于机制的治疗发达。在此应用程序中，我们假设针对TRPA1离子通道后暴露后将改善氯的急性肺，心血管和神经系统作用，导致降低发病率和改善的恢复。 TRPA1是一种化学刺激受体引起的疼痛，水肿，血管舒张，心律不齐，炎症和白细胞浸润。我们在小鼠的初步研究表明TRPA1 抑制剂，当给予氯后暴露时，可以防止氯诱导的血液下降氧合，改善肺功能并减轻炎症。在这里，我们建议测试第三代TRPA1抑制剂的疗效，该抑制剂被发现阻断了小鼠，人类和猪TRPA1，在氯气吸入损伤的小鼠和猪模型中，目的是开发这一点复合作为未来的人类对策。提出了以下目的：目标1：屏幕潜力第三代TRPA1抑制剂在CL2气体吸入损伤的小鼠模型中的治疗作用。目标2：确定猪中TRPA1抑制剂的药代动力学和毒理学特性。目标3：测试TRPA1 在氯气吸入损伤的猪模型中抑制剂