Blocking Arsenicals-induced Cutaneous Injury

阻止砷引起的皮肤损伤

基本信息

批准号：
9750839
负责人：
Mohammad Athar
金额：
$ 73.35万
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：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750839
关键词：
Acids Acute Amines Animal Model Antidotes Antioxidants Area Arsenic Arsenicals Attenuated Biological Biological Assay Biological Markers Biological Models Blood capillaries British Bulla Carrier Proteins Categories Cell Degranulation Chelating Agents Chemical Agents Chemical Warfare Chemical Warfare Agents Chemicals Clinical Cutaneous Cysteine DNA Alkylation DNA Damage Data Dermal Dermatology Development Digestion Dose Edema Effectiveness Eicosanoids Epidermis Erythema Event Exposure to Extravasation FDA approved Family suidae Felis catus Filament Glutathione Glycerol Hair Health protection Hepatic Tissue Human Infiltration Inflammation Inflammatory Inflammatory Response Injury Intercept Kinetics Lead Lesion Leukocytes Liquid substance Lung Mediating Miniature Swine Modeling Molecular Molecular Biology Molecular Chaperones Molecular Target Molecular Weight Mus Mustard Agent Organ Outcome Oxidative Stress Pain Pathogenesis Pathway interactions Penetration Peptide Hydrolases Population Process Production Protective Agents Proteins Reaction Reactive Nitrogen Species Reactive Oxygen Species Regulation Regulatory Pathway Renal Tissue Reporting Research Rupture Scientist Signal Pathway Signal Transduction Skin Skin injury Subcutaneous Tissue Testing Therapeutic Tight Junctions Time Tissues Topical application Toxic effect Toxicology United States National Institutes of Health Vesicants Vesicle Visual War Water attenuation base chemical threat chemokine cytokine diphenyl experience experimental study in vitro Assay inhibitor/antagonist interest keratinocyte lewisite macrophage mast cell mouse model novel occludin pre-clinical prevent programs protein transport public health relevance response screening skin barrier skin lesion small molecule systemic toxicity translational approach water channel

项目摘要

DESCRIPTION (provided by applicant): Arsenicals, such as lewisite, diethylchloroarsine, diphenyl chlorarsine, and diphenyl cyanoarsine have been identified as potential war-threat agents, which could be used in chemical warfare. Topical exposure to these agents is known to result in severe cutaneous blistering and inflammation. In this application, we will test whether these arsenicals as listed above cause similar multiple cutaneous blistering and inflammatory effects in murine (haired but shaved) and mini-pig models as reported in humans. We will also investigate the molecular mechanisms by which these effects are manifested in these animal model systems. Our preliminary data indicate that in hairless murine model arsenicals by penetrating skin, rupture the cutaneous barrier functions as a consequence of disruption of proteins associated with tight junctions and water/glycerin transport. These effects are mediated mainly via activation of hippo signaling pathway protein, Yap besides others. Our data also show that the acute inflammation is mediated through the activation of unfolded protein response (UPR) signaling. UPR pathway is triggered by the arsenicals-dependent reactive oxygen species (ROS) production and activation of DNA damage response signaling. Based on these preliminary results, we will unravel whether crosstalk between these intricate signaling pathways results in the pathogenesis of painful blisters and inflammation. Based on these novel data, it is also tempting to investigate whether blocking these molecular targets by small molecules such as UPR signaling inhibitors also known as chemical chaperones, 4- phenylbutyric acid and salubrinal alone or in combination with arsenic chelator, British anti-lewisite (BAL) or antioxidant N-acetyl cysteine may intercept these effects. This will provide a molecular pathogenesis-based translational approach to develop effective interceptors/antidotes for blocking painful severe skin damage following cutaneous exposure to these chemicals. We are also proposing to test whether cutaneous exposure to these chemicals manifests systemic damage and whether topical application of these antidotes can prevent systemic effects of these chemicals. Three specific aims, each with their own milestones, are proposed to unravel the mechanism of pathogenesis by arsenicals in two animal models and to develop potential antidotes against these agents with defined window of their effectiveness. It is highly likely thatif found effective, the lead compounds based on their known toxicity profile and FDA approved use for other cutaneous blistering and inflammation-unrelated conditions can easily be approved. The outcome of the proposed research is likely to have a significant impact on human health protection in the unfortunate event of mass population exposure to this category of war-threat chemicals.

描述（由应用提供）：砷，例如Lewisite，二乙基氯氨酸，二苯基氯氨酸和二苯基氰基氨基菌氨基已被确定为潜在的威胁性威胁性药物，可用于化学战。众所周知，对这些药物的局部暴露会导致严重的皮肤起泡和炎症。在此应用中，我们将测试上面列出的这些砷是否会导致鼠（头发但剃光）和人类报道的迷你猪模型在鼠（头发但剃光）中产生类似的皮肤发泡和炎症作用。我们还将研究这些作用在这些动物模型系统中表现出来的分子机制。我们的初步数据表明，在无毛鼠模型中，砷通过穿透皮肤而破裂，皮肤屏障的作用是由于破坏与紧密连接和水/甘油传输相关的蛋白质的破坏。这些作用主要是通过激活河马信号通路蛋白的激活来介导的。我们的数据还表明，急性炎症是通过激活展开的蛋白质反应（UPR）信号传导介导的。 UPR途径是由砷依赖性的活性氧（ROS）产生和DNA损伤响应信号传导激活触发的。基于这些初步结果，我们将解开这些复杂的信号通路之间的串扰是否导致疼痛的水泡和炎症的发病机理。基于这些新的数据，还很容易研究小分子（例如UPR信号传导抑制剂）也称为化学链酮，4-苯基丁基酸和单独的盐酸盐，还是与砷螯合剂，英国抗lewisite（BAL）或抗氧化物n-氧化物可能互动这些效果。这将提供一种基于分子发病机理的转化方法，以开发有效的拦截器/抗焦点，以阻止皮肤接触这些化学物质后疼痛的严重皮肤损伤。我们还建议测试皮肤暴露于这些化学物质是否表现出系统性损害，以及这些解毒剂的局部应用是否可以防止这些化学物质的全身作用。提出了三个具体目标，每个目标都有自己的里程碑，以揭示两个动物模型中砷的发病机理的机制，并以其有效性的定义窗口开发针对这些药物的潜在解毒剂。如果发现有效的话，很有可能会根据其已知的毒性概况和FDA批准的其他皮肤泡沫和炎症无关的条件使用的铅化合物很容易获得批准。拟议研究的结果可能会对人类健康保护产生重大影响，因为不幸的是大量人口暴露于这类威胁性的化学物质。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide-mediated impairment of macrophage innate immune functions.

激活转录因子 4 是三氧化二砷介导的巨噬细胞先天免疫功能受损的发病机制的基础。

DOI：
10.1016/j.taap.2016.07.015
发表时间：
2016
期刊：
Toxicology and applied pharmacology
影响因子：
3.8
作者：
Srivastava,RiteshK;Li,Changzhao;Wang,Yong;Weng,Zhiping;Elmets,CraigA;Harrod,KevinS;Deshane,JessyS;Athar,Mohammad
通讯作者：
Athar,Mohammad

Biological and environmental hazards associated with exposure to chemical warfare agents: arsenicals.