UAB Research Center of Excellence in Arsenicals

阿拉巴马大学砷化合物卓越研究中心

• 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
• 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

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.

在世界各地，发泡剂被开发为化学武器，以削弱军民人口 第一次世界大战/第二次世界大战期间，这些化学物质会在皮肤中引起迅速和严重的疼痛、炎症和起泡反应。 这些毒剂包括芥末和兵工厂。其中，硫磺、芥末和路易氏剂被武器化为 单一的药物以及两种药物的混合物。唯一已知的武器解毒剂是英国反路易斯安(BAL)， 这并不是很有效，而且本身就是剧毒的。砷化合物的分子发病机制仍然很差。 理解，这也是开发基于机制的解毒剂以缓解 这些化学物质的毒性。因此，这个U54中心的主要目标是发展基于机制的高度 与化学战有关的武器的有效解毒剂，即路易氏剂、二苯氯砷、 二苯基氰基砷和二乙基氯砷(NIH中和计划优先考虑的)。科学的 这项调查的前提是强有力和令人信服的初步数据表明，表观遗传学 分子信号通路的调节调节砷化合物介导的异常和健壮皮肤的发生 炎症和组织损伤。这些数据还表明，溴域4(BRD4)的招募 诱导基因启动子区域可能参与砷中毒多器官损伤的发病机制 损伤包括皮肤、肺和肾脏。为了验证这一假设，我们开发了一个小鼠模型 概述了在《暴露的》中描述的这些军火药的组织损伤的急性反应和延迟反应 人类。提出了三个具体目标。在特定的目标-1中，研究的重点是充分描述动物的特征 砷化合物致皮肤急性和迟发性皮肤、肺、肾损害模型的建立 暴露在这些化学发泡剂中。这将通过定义分子生物标记物和表观遗传学来实现 与损伤进展相关的痕迹。特定的AIM-2将定义分子机制 砷化合物的毒性，目的是开发新的基于机理的药物抑制剂， 减轻砷化合物的毒性，包括皮肤、肺和肾脏损伤。关于特定目标-3的研究是相关的 从以下方面确定BDR4药物抑制剂有效治疗干预的窗口 抑制皮肤暴露于这些化学物质后对皮肤、肺和肾脏的损害。结果是 这项研究将导致范式转变，发现针对阿森纳的解毒剂，可以有效地阻止 多器官损害、发病率和死亡率。这些抑制剂也可以有效地对抗其他类似的 化学制品。此外，在发现新型分子靶标的基础上，合成并表征了小分子化合物 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送到 在大规模因果关系的情况下，由FDA批准的可自动注射的设备进行皮下注射。因此，这些努力将 显著增强应对发泡剂暴露于公众或士兵的医疗反应能力 恐怖袭击或化学战期间。