The Initiation of Vesicant Skin Injury at a Single Cell Level

单细胞水平上起泡性皮肤损伤

基本信息

批准号：
10708030
负责人：
Bogi Andersen
金额：
$ 23.6万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708030
关键词：
Abbreviations Acetylcysteine Animal Model Antioxidants Arsenic Arsenicals Basal lamina Biochemical Bulla Cells Chemical Structure Chemical Warfare Chromatin Collagen Cyclic GMP-Dependent Protein Kinases Dermal Epidermis Foundations Genes Genetic Transcription Genomics Goals Histologic Human Image Imiquimod Injury Interferons Knowledge Langerhans cell Late Effects Lead Mechlorethamine Metabolic Metabolism Methods Modeling Monitor Mus Mustard Mustard Compounds Mustard Gas Nature Nitric Oxide Nitrogen Nuclear Oxidants Oxidative Stress Oxides Oxygen Pathogenesis Pathogenicity Peroxonitrite Phase Publishing Reactive Nitrogen Species Reactive Oxygen Species Research Role Skin Skin injury Skin repair Structure Sulfides Superoxide Dismutase Technology Terrorism Testing Time Toxic effect Transplantation Vesicants Work cell injury cobinamide effectiveness testing efficacy testing experimental study fluorescence lifetime imaging in vivo in vivo evaluation in vivo fluorescence innovation insight keratinocyte lewisite mouse model novel therapeutic intervention novel therapeutics oxidative damage response single-cell RNA sequencing skin damage tool wound healing

项目摘要

Abstract Sulfur mustard (mustard gas) and arsenicals such as lewisite are major threats as chemical warfare or terrorist agents. Despite different chemical structures, both types of agents lead to similar skin damage with large blisters and wounds that heal slowly, raising the specter of shared pathogenic mechanisms. In this proposal, we will investigate the role of oxidant skin injury as a shared mechanism in mustard and arsenical vesicant injury, employing nitrogen mustard and phenylarsine oxide as surrogates for sulfur mustard and lewisite, respectively. Although major advances have been made in vesicant research, we still do not have effective counter agents. This may be in part due to lack of full understanding of the pathogenesis of vesicants. The overarching hypothesis of this proposal is that defining the early effects of vesicants in vivo at subcellular and single cell levels will refine our understanding of the role of oxidative stress in vesicant skin injury and lead to new therapeutic strategies. We will also test the hypothesis that cobinamide, a highly effective and versatile antioxidant that neutralizes both reactive oxygen and nitrogen species, will be effective as a counter-agent and as means to understand better the role of oxidative stress in nitrogen mustard- and phenylarsine oxide-induced vesicant injury. The specific aims are: 1) To understand the initiation of nitrogen mustard- and phenylarsine oxide-induced skin injury at a single cell level. We will use in vivo fluorescence lifetime imaging (FLIM) and single cell RNA sequencing to gain a new view on the initiation of vesicant injury and the role of oxidative stress in the pathogenesis. 2) To define the efficacy of cobinamide against nitrogen mustard- and phenylarsine oxide-induced vesicant skin injury. We will test the efficacy of cobinamide against nitrogen mustard- and phenylarsine oxide-induced vesicant skin injury in mice. Due to differences between mouse and human skin, we will also investigate vesicant mechanisms in transplanted human skin. These studies are significant and innovative because they use state of the art tools to investigate a gap in our knowledge about the role of oxidative stress in the initiation of mustard and arsenical vesicant injury and because they test for the first time cobinamide, a highly effective antioxidant that is bifunctional for reactive oxygen and nitrogen species.

抽象的硫磺（芥末气）和诸如路易斯特等砷是化学战或恐怖分子等主要威胁代理商。尽管化学结构不同，但两种类型的药物都会导致皮肤损伤相似并恢复缓慢的伤口，增加了共同致病机制的幽灵。在此提案中，我们将研究氧化剂皮肤损伤作为芥末和砷囊泡损伤中的共享机制的作用，分别用氮芥末和氧化苯胺作为硫酸盐和刘易斯石的替代物。尽管在Vesicant研究中已经取得了重大进展，但我们仍然没有有效的反击代理。这可能部分是由于缺乏对囊泡的发病机理的完全理解。总体假设该建议的是，在亚细胞和单细胞水平上定义体内囊泡的早期作用将完善我们对氧化应激在囊泡皮肤损伤中的作用的理解并导致新的治疗策略。我们还将检验以下假设，即哥竞胺是一种高效且多才多艺的抗氧化剂，可中和活性氧和氮种将是一种反代理，可以更好地理解更好的方法氧化应激在氮芥末酱和苯胺氧化物诱导的囊泡损伤中的作用。具体目的是：1）了解氮芥末芥末和氧化苯胺诱导的皮肤损伤的启动在单个单元格级别。我们将使用体内荧光寿命成像（FLIM）和单细胞RNA测序为了对囊泡损伤的启动以及氧化应激在发病机理中的作用获得新的看法。 2）到定义核酰胺对氮芥末芥末和苯烷氧化物诱导的囊泡的疗效皮肤损伤。我们将测试核酰胺对氮芥末和氧化苯胺诱导的疗效小鼠的囊泡皮肤损伤。由于小鼠和人皮之间的差异，我们还将研究囊泡移植的人皮中的机制。这些研究具有重要和创新性，因为它们使用我们了解氧化应激在芥末启动中的作用的差距的艺术工具和砷囊泡损伤，并且因为它们首次测试了核酰胺，所以高效的抗氧化剂这对于活性氧和氮种是双功能的。