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：
10249107
负责人：
Mohammad Athar
金额：
$ 376.03万
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/10249107
关键词：
Accidents Acute Animal Model Anti-Inflammatory Agents 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 Injury to Kidney 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 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 therapeutically effective tissue injury 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.

起泡剂是作为化学武器而开发的，目的是在世界大战期间削弱军队和平民的力量。第一次/第二次战争中，这些化学物质会引起皮肤快速而严重的疼痛性炎症和起泡反应。这些制剂包括芥子和砷。其中硫芥和路易斯被武器化为单一药剂以及两者的混合物。唯一已知的砒霜解毒剂是英国反刘易斯剂（BAL），这不是很有效，而且本身有剧毒。砷的分子发病机制仍不清楚理解，这也是开发基于机制的解毒剂以减轻这些化学品的毒性。因此，这个U54中心的主要目标是发展基于机制的高度对抗化学战相关砷的有效解毒剂，即刘易斯、二苯基氯胂、二苯基氰胂和二乙基氯胂（由 NIH CounterACT 计划优先考虑）。科学的这项研究的前提在于强有力且令人信服的初步数据，表明表观遗传分子信号通路的调节调节砷介导的异常和强健皮肤的发作炎症和组织损伤。这些数据还表明，溴结构域 4 (BRD4) 的招募诱导基因启动子区可能参与砷介导的多器官疾病的发病机制损害包括皮肤、肺和肾。为了验证这一假设，我们开发了一种小鼠模型概括了暴露中描述的这些砷的组织损伤急性和延迟反应人类。提出了三个具体目标。在具体目标 1 中，研究的重点是充分表征动物砷介导的皮肤后急性和迟发性皮肤、肺和肾损伤模型接触这些化学起泡剂。这将通过定义分子生物标志物和表观遗传来实现与损伤进展相关的标记。具体目标2将定义分子机制砷的毒性，目标是开发基于机制的新型药理抑制剂减轻砷的毒性，包括皮肤、肺和肾损伤。具体目标3的研究是相关的定义 BDR4 药物抑制剂有效治疗干预的窗口抑制皮肤接触这些化学物质后的皮肤、肺和肾损伤。结果这项研究将导致范式转变，发现可以有效阻止砷的解毒剂多器官损伤、发病率和死亡率。这些抑制剂还可以提供针对其他类似药物的功效化学品。此外，基于新分子靶点的发现，小分子药物的合成和表征分子将由药物发现和开发核心完成。这些解毒剂可以很容易地提供在发生大规模因果关系时，通过 FDA 批准的自动注射装置进行皮下注射。因此，这些努力将显着提高医疗响应能力，以解决在公共场所或士兵中暴露出疱疹的问题恐怖袭击或化学战期间。