Project 1: Novel Pharmacological Inhibitors of Chemical Vesicants-mediated Cutaneous Injury

项目1：化学糜烂介导的皮肤损伤的新型药理抑制剂

• 批准号: 10249113
• 负责人: Mohammad Athar
• 金额: $ 71.91万
• 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/10249113
• 关键词: Ablation; Acetylation; Acute; Affect; Animals; Antidotes; Arsenic; Arsenicals; Bromodomain; Bulla; Centers of Research Excellence; Cessation of life; Chemicals; Clinical; Coupled; Cutaneous; DNA Alkylation; Data; Data Analyses; Development; Dose; Edema; Epigenetic Process; Erythema; Exposure to; Genes; Genetic; Genetic Transcription; Glutathione; Goals; Histone Acetylation; Histones; Human; Human Pathology; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Iraq; Kinetics; Knowledge; Lysine; Massive Parallel Sequencing; Mediating; Miniature Swine; Modeling; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; Mustard Agent; Oxidative Stress; Pain; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Phosphorylation; Population; Process; Production; Prostaglandins; Proteins; Reactive Oxygen Species; Reader; Regulation; Role; Series; Signal Transduction; Skin; Skin injury; Small Interfering RNA; Structure; Syria; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Topical application; Toxic effect; United States National Institutes of Health; Vesicants; War; World War II; animal tissue; base; chemical threat; chromatin immunoprecipitation; chromatin remodeling; comparative; cytokine; effective intervention; endoplasmic reticulum stress; in vitro Assay; in vivo; inhibitor/antagonist; keratinocyte; lewisite; lung injury; mouse model; novel; programs; response; skin lesion; skin organogenesis; small molecule; spatiotemporal; tissue injury; weapons

The class of chemical war-threat agents known as vesicants include among others arsenicals and mustard agents. Stockpiles of weaponized arsenic-based vesicants developed for World War II still exist. Recently, vesicants have been used against civilian populations in Iraq and Syria and caused extensive morbidities and a few casualties. Cutaneous exposure to arsenicals causes vesicular skin lesions, blisters, and painful cutaneous inflammation, which progresses to multi-organ tissue disruption and death. Four major arsenicals, lewisite, diphenylchlorarsine, diphenylcyanoarsine and diethylchloroarsine, have been identified as potential threat chemicals by NIH CounterACT program for which antidotes/agents are highly sought. However, the mechanisms by which these arsenicals manifest such robust deleterious effects in the skin remain undefined. We have recently developed a highly sensitive murine model of cutaneous arsenical exposure, which recapitulates skin pathology of humans exposed to these chemicals. Our preliminary studies indicate that the acute inflammatory and tissue damaging effects caused by arsenicals are mediated through the rapid onset of epigenetic modifications and chromatin remodeling via histone lysine hyperacetylation. In this regard, bromodomain 4 (BRD4), a reader of histone acetylation marks is considered to be one of the potent transcriptional regulator of inducible inflammatory genes besides others. In this Project-I of U54, we propose to investigate histone acetylation-based epigenetic alterations involved in the molecular pathogenesis of skin lesions and development of antidotes that can block arsenical-induced cutaneous injury. Three specific aims are proposed: 1: To characterize histone acetylation and chromatin remodeling-associated with arsenical exposure. This data will provide a correlation between the spatiotemporal regulation of histone acetylation and underlying arsenicals- induced cutaneous injury. After establishing these changes in murine skin we will confirm the molecular pathogenesis of acute skin injury by arsenicals in minipig; 2: To unravel the molecular mechanism by which arsenicals-mediated histone acetylations affect inflammatory and blistering responses. We will probe the mechanisms by which arsenicals induce BRD4 activation. 3: To define the window of therapeutic intervention of arsenicals-mediated tissue damage by administering BRD4 inhibitors. Our goal is to fully characterize the kinetics of action and assess the therapeutic window of time (30, 60 or 120 min after exposure to arsenicals) in which these BRD4 inhibitors are able to reverse arsenical-induced molecular changes and underlying skin inflammation/blistering. This project will integrate with projects II, III, and scientific cores as animal tissues will be shared from topically exposed animals. Therapies successful in reversing skin inflammation/damage will also be verified for the diminution of lung and kidney injury. Successful completion of this proposal will lead to a paradigm shift in the existing knowledge of arsenicals' toxicity and development of novel series of mechanism- based antidotes.

被称为囊泡药的化学战争剂等类别包括武库和芥末 代理商。为第二次世界大战开发的基于砷的武器的库存仍然存在。最近， 在伊拉克和叙利亚的平民种群中，囊泡人已被使用，并引起了广泛的病态和 几乎没有伤亡。皮肤暴露于砷中会导致囊泡皮肤病变，水泡和皮肤疼痛 炎症，发展为多器官组织破坏和死亡。四个主要的砷，路易斯特， 二苯基氯氨氨酸，二苯基丙烯酸酯和二乙基氯苯胺已被确定为潜在的威胁 由NIH抵抗计划的化学药品高度寻求解毒剂/药物的化学物质。但是，机制 这些砷在皮肤中表现出这种强大的有害作用仍然不确定。我们有 最近开发了一种高度敏感的皮肤砷暴露模型，该模型概括了皮肤 暴露于这些化学物质的人类的病理学。我们的初步研究表明急性炎症 砷引起的组织破坏作用是通过表观遗传的快速开始介导的 通过组蛋白赖氨酸高乙酰化修饰和染色质重塑。在这方面，溴结构域4 （BRD4），组蛋白乙酰化标记的读者被认为是有效的转录调节因子之一 除其他人以外，诱导性炎症基因。在U54 I项目中，我们建议研究组蛋白 乙酰化基于乙酰化的表观遗传学改变涉及皮肤病变的分子发病机理 可以阻止砷引起的皮肤损伤的解毒剂。提出了三个具体目标：1： 表征组蛋白乙酰化和与砷暴露相关的染色质重塑。这些数据将 提供了组蛋白乙酰化的时空调节与潜在的砷之间的相关性 - 诱发皮肤损伤。在鼠皮中建立这些变化后，我们将确认分子 小动物中砷造成急性皮肤损伤的发病机理； 2：揭开分子机制 砷介导的组蛋白乙酰化会影响炎症和起泡反应。我们将探究 砷诱导BRD4激活的机制。 3：定义治疗干预的窗口 通过施用BRD4抑制剂，砷介导的组织损伤。我们的目标是完全表征 动作动力学并评估时间的治疗窗口（暴露于砷后30、60或120分钟） 这些BRD4抑制剂能够逆转砷诱导的分子变化和潜在的皮肤 炎症/起泡。该项目将与II，III和科学核心的项目集成，因为动物组织将 从局部暴露的动物中分享。成功逆转皮肤炎症/损害的疗法也将 可以验证肺和肾脏损伤的减少。成功完成此建议将导致 范式的范式转移了对砷的毒性的现有知识和新型机制的发展的发展 基于解毒剂。