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: 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
• 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

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.

在二战期间，发疱剂作为化学武器被开发出来，用来削弱军队和平民的力量。 War-I/II，因为这些化学物质会导致皮肤迅速而严重的疼痛性炎症和起泡反应。 这些制剂包括吗啡和砷剂。其中芥子气和路易氏剂被用作武器， 单一试剂以及两者的混合物。唯一已知的砷剂解毒剂是英国抗路易氏剂（BAL）， 其不是非常有效并且本身是高毒性的。砷剂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减轻 这些化学物质的毒性。因此，该U 54中心的主要目标是开发基于机制的高度 对化学战相关砷即路易氏剂，二苯氯胂， 二苯氰胂和二乙基氯胂（如NIH CounterACT计划优先考虑的）。科学 这项研究的前提在于强有力的和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稳健的皮肤 炎症和组织损伤。这些数据还表明，布罗莫结构域4（BRD 4）的募集对人的免疫应答具有显著的抑制作用。 诱导基因的启动子区可能参与砷剂介导的多器官损伤的发病过程 包括皮肤、肺和肾的损害。为了验证这一假设，我们开发了一种小鼠模型， 概括了这些砷剂暴露后的急性和延迟的组织损伤反应， 人类提出了三个具体目标。在具体目标1中，研究重点是充分表征动物 砷剂介导的急性和迟发性皮肤、肺和肾损伤模型 暴露在这些化学起疱剂中这将通过定义分子生物标志物和表观遗传学来实现。 与损伤进展相关的标记。具体目标-2将定义 目的是开发新的基于机制的药理学抑制剂， 减轻砷剂的毒性，包括皮肤、肺和肾损伤。具体目标-3中的研究是相关的 在以下方面定义BDR 4的药理学抑制剂的有效治疗干预的窗口： 抑制皮肤暴露于这些化学品后的皮肤、肺和肾损伤。成果 这项研究的结果将导致范式转变，发现砷的解毒剂， 多器官损伤、发病率和死亡率。这些抑制剂也可以提供针对其他类似的 化学品此外，基于新的分子靶点的发现，小分子的合成和表征， 分子将由药物发现和开发中心完成。这些解毒剂可以很容易地 如果是大规模因果关系，则通过自动注射FDA批准的器械皮下注射。这些努力将 大大提高医疗反应能力，以解决公众或士兵接触水疱剂的问题， 恐怖袭击或化学战期间。