The Role of Macrophages in Vesicant Skin Injury and Repair

巨噬细胞在水疱性皮肤损伤和修复中的作用

• 批准号: 10667174
• 负责人: TIMOTHY J KOH
• 金额: $ 23.69万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-13 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667174
• 关键词: Address; Antidiabetic Drugs; Arsenic; Arsenicals; Bioinformatics; Biological Assay; Bone Marrow; Bulla; C57BL/6 Mouse; Cells; Chemical Agents; Chemical Warfare Agents; Data; Data Set; Development; Erythema; Experimental Designs; Exposure to; FDA approved; Flow Cytometry; Future; Glyburide; Goals; Grant; Host Defense; Human; Immunohistochemistry; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Knockout Mice; Knowledge; Laboratories; Macrophage; Mechlorethamine; Metabolic; Methods; Miniature Swine; Modeling; Mus; Mustard; Mustard Gas; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Oral; Oxides; Pathway interactions; Play; Protocols documentation; Recording of previous events; Research; Research Contracts; Research Personnel; Resolution; Role; Safety; Sampling; Signal Transduction; Site; Skin; Skin injury; Skin repair; Skin wound healing; Techniques; Testing; Therapeutic; Tissues; Training; United States National Institutes of Health; Up-Regulation; Vesicants; chemical countermeasure; chemical threat; cytokine; experimental study; healing; improved; inhibitor; insight; keratinocyte; lewisite; monocyte; necrotic tissue; neutrophil; novel; programs; protocol development; prototype; receptor; repaired; response; single-cell RNA sequencing; skin damage; skin wound; tissue injury; tissue repair; wound; wound healing; wound response

Abstract Chemical warfare agents such as mustards and arsenicals cause skin damage characterized by erythema, inflammation, and skin blistering, followed by a prolonged healing period. Although inflammatory cells and related cytokines are known to be increased in skin exposed to both mustards and arsenicals, similarities and differences in the roles of subsets of these cells in mustard- or arsenical-induced skin damage, as well as subsequent healing, remain to be elucidated. A goal of this proposal is to develop capacity to study the role of the inflammatory response, particularly the macrophage response, using cutting edge single cell techniques, in mustard and arsenical skin injury. This will include generating preliminary data with prototype agents and planning for experiments with restricted agents to support future NIH CounterACT grant submissions in the following aims: for Specific Aim 1, we will define the response of wound inflammatory cell subsets to vesicant skin injury using nitrogen mustard (NM) as prototype mustard and phenylarsine oxide (PAO) as prototype arsenical. For Specific Aim 2, since we and others have identified NLRP-3 is a key regulator of the inflammatory response to skin injury, we will determine the role of the NOD-Like Receptor (NLRP)-3 inflammasome in vesicant skin injury and repair. For Specific Aim 3, we will develop a relationship with MRIGlobal to perform studies with restricted vesicants. MRIGlobal is a contract research organization whose laboratory is approved for use of more potent restricted vesicants. Successful completion of this project will 1) bring a new skin wound healing research group into the chemical countermeasure field, 2) improve understanding of the role of inflammatory cell subsets in the response to vesicant injury, 3) establish the importance of the NLRP-3 inflammasome in regulating this inflammatory response and test an NLRP-3 inhibitor as a potential countermeasure and 4) develop a relationship with MRIGlobal for future studies using restricted vesicants. Ultimately, we plan to use knowledge generated by our research to develop novel countermeasures that target the inflammatory response.

摘要 化学战剂，如芥子和兵器，会造成皮肤损伤，其特征是红斑， 发炎，皮肤起泡，随后是长时间的愈合期。虽然炎性细胞和 已知接触芥子和砷的皮肤中相关的细胞因子会增加，相似和 这些细胞亚群在芥末或砷诱导的皮肤损伤中的作用差异，以及 随后的愈合，仍有待阐明。这项提议的一个目标是发展能力，研究 炎症反应，特别是巨噬细胞反应，使用尖端的单细胞技术，在 芥末和砷的皮肤损伤。这将包括使用原型代理生成初步数据和 计划与受限代理进行试验，以支持未来NIH中和拨款申请 以下目标：为了特定的目标1，我们将定义创面炎症细胞亚群对发泡剂的反应 以氮芥末(NM)为原型，以氧化苯砷(PAO)为原型的皮肤损伤 阿森纳。对于特定的目标2，由于我们和其他人已经确定NLRP-3是 在皮肤损伤的炎症反应中，我们将确定NOD样受体(NLRP)-3的作用 发泡性皮肤损伤与修复中的炎症性小体。为了实现具体目标3，我们将与 核磁共振全球公司对限制发泡剂进行研究。MRIGlobal是一家合同研究机构，其 实验室被批准使用更有效的限制性发泡剂。该项目的成功完成将1) 将新的皮肤伤口愈合研究小组引入化学对抗领域，2)改进 了解炎症细胞亚群在发泡剂损伤反应中的作用，3)建立 NLRP-3炎症体在调节炎症反应和检测NLRP-3中的重要性 作为一种潜在的对策和4)发展与磁共振全球为未来的研究使用的关系 限制性发泡剂。最终，我们计划利用我们的研究产生的知识来开发小说 针对炎症反应的对策。