Research Project I - Vesicant-Induced Skin Injury

研究项目1.糜烂性皮肤损伤 主要人员： Donald Gerecke博士，罗格斯大学药学院副教授 Jeffrey D.拉斯金博士，罗格斯大学公共卫生学院教授 项目总结/摘要 硫芥（双-2-氯乙基硫醚，SM）和氮芥（双-2-氯乙基乙胺，NM）是 已被用作化学武器的起泡剂;它们是皮肤中的强效起泡剂。 本研究项目的总体目标是阐明芥子气对皮肤损伤的基本机制， 目标是确定治疗干预和药物开发的新靶点。我们发现了一 皮肤损伤和由vesciant和内源性大麻素系统诱导的炎症之间的高度新颖的联系， 一种普遍存在的信号系统，调节细胞生长和分化，下调炎症 应答内源性大麻素由内源性配体（例如，花生四烯酰胺[AEA]和2-花生四烯酰基- 甘油，[2-AG]），大麻素受体（例如，G蛋白偶联的CB 1和CB 2受体），以及代谢 调节内源性大麻素生物合成的酶（例如，N-酰基转移酶、磷脂酶）和 降解（例如，脂肪酸酰胺水解酶[FAAH]，单酰基甘油脂肪酶[MAGL]）。局部应用 SM或NM对小鼠皮肤的作用引起了显著的和持续的表达上调， 内源性大麻素降解酶FAAH和结合内源性大麻素的受体蛋白，包括CB 1， CB 2和过氧化物酶体增殖物激活受体-α（PPARα）。重要的是，内源性大麻素已经被 显示在人类皮肤疱液中积累，表明它们可能参与了病理生理学 vesicants的反应。我们假设内源性大麻素调节炎症和伤口愈合， 皮肤暴露于吗啡后，因此，内源性大麻素系统可以被靶向， 制定对策。我们进入高级开发阶段的主要主导产品是 FAAH。我们的目的是评估内源性大麻素系统在水疱剂诱导的皮肤损伤中的作用， 伤口愈合和阐明机制，通过它muplatin调节角质形成细胞表达的 内源性大麻素系统我们还将评估一种高度新颖的药物输送系统，以提高我们的药物的疗效。 铅化合物我们的研究将提供关于内源性大麻素在 病理生理的发泡剂引起的皮肤毒性，并导致更有效的发展 对策

Research Project 1. Vesicant-induced Skin Injury Key personnel: Donald Gerecke, Ph.D., Associate Professor, Rutgers University School of Pharmacy Jeffrey D. Laskin, Ph.D., Professor, Rutgers University School of Public Health Project Summary/Abstract Sulfur mustard (bis-2-chloroethyl sulfide, SM) and nitrogen mustard (bis-2-chloroethyl ethylamine, NM), are vesicants that have been adapted for use as chemical weapons; they are potent blistering agents in the skin. The overall goal of this research project is to elucidate basic mechanisms of mustard damage to the skin with the objective of identifying new targets for therapeutic intervention and drug development. We discovered a highly novel link between skin injury and inflammation induced by vesciants and the endocannabinoid system, a ubiquitous signaling system that regulates cell growth and differentiation and down regulates inflammatory responses. Endocannabinoids consist of endogenous ligands (e.g., anandamide [AEA] and 2-arachidonoyl- glycerol, [2-AG]), cannabinoid receptors (e.g., the G-protein coupled CB1 and CB2 receptors), and metabolic enzymes that regulate endocannabinoid biosynthesis (e.g., N-acyltransferases, phospholipases) and degradation (e.g., fatty acid amide hydrolase [FAAH], monoacylglycerol lipase [MAGL]). Topical application of either SM or NM to mouse skin caused a marked and persistent upregulation of expression of the endocannabinoid degrading enzyme, FAAH, and receptor proteins that bind endocannabinoids including CB1, CB2 and peroxisome proliferator-activated receptor-α (PPARα). Importantly, endocannabinoids have been shown to accumulate in human skin blister fluid, suggesting that they may be involved in the pathophysiologic response to vesicants. We hypothesize that endocannabinoids regulate inflammation and wound healing in the skin following exposure to mustards and thus, the endocannabinoid system can be targeted for the development of countermeasures. Our key lead product entering advanced development is an inhibitor of FAAH. Our aims are to assess the role of the endocannabinoid system in vesicant-induced skin injury and wound healing and elucidate mechanisms by which mustards modulate keratinocyte expression of the endocannabinoid system. We will also evaluate a highly novel drug delivery system to improve efficacy of our lead compound. Our studies will provide key information on the role of endocannabinoids in the pathophysiology of vesicant-induced skin toxicity and lead to the development of more effective countermeasures.