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:
- 金额:$ 376.02万
- 依托单位:
- 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:
- 关键词:AccidentsAcuteAnimal ModelAnti-Inflammatory AgentsAnti-inflammatoryAntidotesArsenicalsAsiaAttenuatedBritishBromodomainBullaCenters of Research ExcellenceChelating AgentsChemical InjuryChemical ModelsChemical WarfareChemical WeaponsChemicalsCitiesClientComplexCutaneousDangerousnessDataDepartment of DefenseDevelopmentDevicesEpigenetic ProcessEtiologyExposure toFDA approvedGenesGermanyGoalsHistone AcetylationHumanInflammationInflammatoryInjectableInjuryInvestigationItalyJapanKansasKidneyLungMediatingMedicalMilitary PersonnelMolecularMolecular TargetMorbidity - disease rateMustardMustard GasOutcome StudyOxidative StressPainPathogenesisPathway interactionsPharmacologyPoisonPopulationPromoter RegionsProteinsPublicationsReaderReportingRiskRussiaSecuritySignal PathwaySignal TransductionSkinSkin injurySoldierStructureSyriaTerrorismTestingTherapeuticTherapeutic InterventionTissuesToxic effectTreatment EfficacyUnited States National Institutes of HealthVesicantsWarWorkWorld War IWorld War IIbasedrug developmentdrug discoveryendoplasmic reticulum stressepigenetic regulationexposed human populationinhibitor/antagonistinterestlewisitelung injurymedical countermeasuremisfolded proteinmolecular markermortalitymouse modelmultiorgan damagenovelprogramsrecruitrenal damageresponsesmall moleculesubcutaneoustherapeutic targetweaponsweb 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mohammad Athar其他文献
Mohammad Athar的其他文献
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{{ truncateString('Mohammad Athar', 18)}}的其他基金
Optimization of Novel Molecular Target-based Drugs for Arsenical Skin Injury
砷皮肤损伤新型分子靶点药物的优化
- 批准号:
10259711 - 财政年份:2020
- 资助金额:
$ 376.02万 - 项目类别:
Optimization of Novel Molecular Target-based Drugs for Arsenical Skin Injury
砷皮肤损伤新型分子靶点药物的优化
- 批准号:
10023318 - 财政年份:2020
- 资助金额:
$ 376.02万 - 项目类别:
Optimization of Novel Molecular Target-based Drugs for Arsenical Skin Injury
砷皮肤损伤新型分子靶点药物的优化
- 批准号:
10700044 - 财政年份:2020
- 资助金额:
$ 376.02万 - 项目类别:
Optimization of Novel Molecular Target-based Drugs for Arsenical Skin Injury
砷皮肤损伤新型分子靶点药物的优化
- 批准号:
10886403 - 财政年份:2020
- 资助金额:
$ 376.02万 - 项目类别:
Core 4: Animal Breeding (UAB) and Exposure Core (MRIGLOBAL)
核心 4:动物育种 (UAB) 和暴露核心 (MRIGLOBAL)
- 批准号:
10249112 - 财政年份:2018
- 资助金额:
$ 376.02万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 376.02万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 376.02万 - 项目类别:
Core 3: Rexinoid Screening and Animal Core
核心 3:Rexinoid 筛选和动物核心
- 批准号:
10263928 - 财政年份:2017
- 资助金额:
$ 376.02万 - 项目类别:
Core 3: Rexinoid Screening and Animal Core
核心 3:Rexinoid 筛选和动物核心
- 批准号:
10493962 - 财政年份:2017
- 资助金额:
$ 376.02万 - 项目类别:
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