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.

抽象的硫芥（芥子气）和砷等砷剂是化学战或恐怖分子的主要威胁代理。尽管化学结构不同，但这两种类型的药剂都会导致类似的皮肤损伤并出现大水泡伤口愈合缓慢，引发了人们对共同致病机制的担忧。在本提案中，我们将研究氧化性皮肤损伤作为芥末和砷疱疹损伤的共同机制的作用，使用氮芥和氧化苯胂分别作为硫芥和路易斯的替代物。尽管起泡剂研究已取得重大进展，但我们仍然没有有效的反剂。这可能部分是由于对出疱剂的发病机制缺乏充分了解。总体假设该提案的主要内容是，在亚细胞和单细胞水平上定义起泡剂在体内的早期作用将完善我们对氧化应激在疱疹性皮肤损伤中的作用的理解并导致新的治疗策略。我们还将测试以下假设：cobinamide，一种高效且多功能的抗氧化剂，可以中和两者活性氧和氮物种，将作为反剂和更好地了解的有效手段氧化应激在氮芥和氧化苯胂诱导的出疱损伤中的作用。具体的目的是： 1) 了解氮芥和氧化苯胂引起的皮肤损伤的起始过程在单细胞水平上。我们将使用体内荧光寿命成像 (FLIM) 和单细胞 RNA 测序获得关于疱疹损伤的起始和氧化应激在发病机制中的作用的新观点。 2) 至确定可滨酰胺对氮芥和氧化苯胂诱导的起泡剂的功效皮肤损伤。我们将测试 Cobinamide 对氮芥和氧化苯胂诱导的效果小鼠的水疱性皮肤损伤。由于小鼠和人类皮肤之间的差异，我们还将研究起泡剂移植人体皮肤的机制。这些研究具有重要意义和创新性，因为它们使用了研究我们关于氧化应激在芥末引发中的作用的知识差距的艺术工具和砷疱疹损伤，因为他们首次测试了cobinamide，一种高效的抗氧化剂它对于活性氧和氮物种具有双功能。