UAB Research Center of Excellence in Arsenicals

阿拉巴马大学砷化合物卓越研究中心

基本信息

批准号：
9767149
负责人：
Mohammad Athar
金额：
$ 376.02万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767149
关键词：
Accidents Acute Animal Model Anti-Inflammatory Agents Anti-inflammatory Antidotes Arsenicals Asia Attenuated British Bromodomain Bulla Centers of Research Excellence Chelating Agents Chemical Injury Chemical Models Chemical Warfare Chemical Weapons Chemicals Cities Client Complex Cutaneous Dangerousness Data Department of Defense Development Devices Epigenetic Process Etiology Exposure to FDA approved Genes Germany Goals Histone Acetylation Human Inflammation Inflammatory Injectable Injury Investigation Italy Japan Kansas Kidney Lung Mediating Medical Military Personnel Molecular Molecular Target Morbidity - disease rate Mustard Mustard Gas Outcome Study Oxidative Stress Pain Pathogenesis Pathway interactions Pharmacology Poison Population Promoter Regions Proteins Publications Reader Reporting Risk Russia Security Signal Pathway Signal Transduction Skin Skin injury Soldier Structure Syria Terrorism Testing Therapeutic Therapeutic Intervention Tissues Toxic effect Treatment Efficacy United States National Institutes of Health Vesicants War Work World War I World War II base drug development drug discovery endoplasmic reticulum stress epigenetic regulation exposed human population inhibitor/antagonist interest lewisite lung injury medical countermeasure misfolded protein molecular marker mortality mouse model multiorgan damage novel programs recruit renal damage response small molecule subcutaneous therapeutic target weapons web site

项目摘要

Vesicants were developed as chemical weapons to debilitate the military and civilian populations during World War-I/II as these chemicals cause rapid and severe painful inflammatory and blistering responses in the skin. These agents include mustards and arsenicals. Among them sulfur mustard and lewisite were weaponized as single agents as well as a mixture of the two. The only known antidote for arsenicals is British Anti-lewisite (BAL), which is not very effective and itself is highly toxic. The molecular pathogenesis of arsenicals remains poorly understood, which is also an important impediment in developing mechanism-based antidotes for mitigating the toxicity of these chemicals. Therefore, the major goal of this U54 Center is to develop mechanism-based highly efficacious antidotes against chemical war relevant arsenicals namely lewisite, diphenylchloroarsine, diphenylcynoarsine and diethylchloroarsine (as prioritized by the NIH CounterACT program). The scientific premise of this investigation lies in the strong and compelling preliminary data demonstrating that epigenetic regulation of molecular signaling pathways regulate arsenicals-mediated onset of aberrant and robust cutaneous inflammation and tissue damage. These data also indicate that recruitment of bromodomain 4 (BRD4) to promotor region of inducible genes could be involved in the pathogenesis of arsenicals-mediated multi-organ damage including skin, lung and kidney. To test this hypothesis, we have developed a murine model that recapitulates the tissue damaging acute as well as delayed responses of these arsenicals described in exposed humans. Three specific aims are proposed. In specific aim-1, studies are focused to fully characterize the animal model of arsenicals-mediated acute and delayed cutaneous, pulmonary and renal damage following skin exposure to these chemical vesicants. This will be achieved by defining molecular biomarkers and epigenetic marks associated with the progression of the damage. Specific aim-2 will define molecular mechanism of arsenicals' toxicity with an objective for developing novel mechanism-based pharmacological inhibitors that can mitigate arsenicals' toxicity including cutaneous, pulmonary and renal injury. Studies in specific aim-3 are related to defining window of effective therapeutic intervention of pharmacological inhibitors of BDR4 in terms of suppressing cutaneous, pulmonary and renal damage following skin exposure to these chemicals. The outcome of this study will lead to paradigm shift discovery of antidotes against arsenicals which could block effectively multi-organ damage, morbidity, and mortality. These inhibitors could also provide efficacy against other similar chemicals. In addition, based on the discovery of novel molecular targets, synthesis and characterization of small molecules will done by the Drug Discovery and Development Core. These antidotes could easily be delivered subcutaneously by auto-injectable FDA approved devices in case of mass causality. Thus these efforts will significantly enhance the medical response capabilities in tackling vesicants' exposure to public or soldiers in a terrorist attack or during chemical warfare.

在世界上，囊泡人是作为化学武器而开发的，以使世界上的军事和平民人口衰弱 WAR-I/II由于这些化学物质会导致皮肤快速而严重的疼痛炎症和起泡反应。这些代理包括芥末和砷。其中，硫磺芥末和刘易斯特被武器化为单一代理以及两者的混合物。唯一已知的砷解毒剂是英国抗Lewisite（BAL），这不是很有效，并且本身是有毒的。砷的分子发病机理仍然很差理解，这也是开发基于机制的解毒剂来减轻机制的重要障碍这些化学物质的毒性。因此，该U54中心的主要目标是高度开发基于机制针对化学战争相关的砷的有效解毒剂，即刘易斯石，二苯基氯苯胺二苯基氯苯胺和二乙基氯苯胺（由NIH抵抗计划优先）。科学这项调查的前提在于强大而引人注目的初步数据表明表观遗传分子信号通路的调节调节烟囱介导的异常和鲁棒皮肤发作炎症和组织损伤。这些数据还表明，招募溴结构域4（BRD4）诱导基因的启动区域可能与砷介导的多器官的发病机理有关损害包括皮肤，肺和肾脏。为了检验这一假设，我们开发了一个鼠模型概括组织破坏性急性以及在暴露中描述的这些砷的延迟反应人类。提出了三个具体目标。在特定的AIM-1中，研究专注于充分表征动物皮肤后，砷介导的急性和延迟皮肤，肺和肾脏损伤的模型暴露于这些化学囊泡。这将通过定义分子生物标志物和表观遗传学来实现与损害进展相关的标记。特定的AIM-2将定义分子机制砷的毒性具有开发基于机制的新型药理抑制剂的目标减轻砷的毒性，包括皮肤，肺部和肾脏损伤。特定AIM-3的研究与以确定BDR4药理学抑制剂有效治疗干预的窗口皮肤暴露于这些化学物质后，抑制皮肤，肺和肾脏损伤。结果这项研究将导致对砷的解毒量的发现，这可能有效地阻止多器官损害，发病率和死亡率。这些抑制剂也可以为其他类似的抑制剂提供疗效化学物质。此外，基于发现新分子靶标的发现，小的合成和表征分子将由药物发现和发育核心完成。这些解毒剂可以轻松传递在大量因果关系的情况下，通过自动注射FDA批准的设备皮下皮下。因此，这些努力将显着增强了解决囊泡人接触公共或士兵的医疗反应能力恐怖袭击或化学战期间。