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Principal Investigator: DONALD R GERECKE
Organization: RBHS-SCHOOL OF PUBLIC HEALTH
Fiscal Year: 2019
Award: $846,767
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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.
Terms: <2-AG><2-arachidonoyl-glycerol><2-arachidonoyl-sn-glycerol><2-arachidonoylglycerol><2-arachidonyl-glycerol><2-arachidonylglycerol><Active Oxygen><Acyltransferase><Advanced Development><Alkylating Agents><Alkylators><Anabolism><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Binding Proteins><Bis(beta-chloroethyl) Sulfide><Bleb><Blister><Body Tissues><Bulla><Bullous Lesion><CB1><CB1 Receptor><CB1R><CB2><CB2 Receptor><CB2R><CNR1 gene><CNR2><CNR2 gene><Cannabinoid Receptor CB1><Cannabinoid Receptor CB2><Cell Communication and Signaling><Cell Signaling><Cellular Expansion><Cellular Growth><Chemical Weapons><Chemicals><Chloramin><Chlorethazine><Chlormethine><Coupled><DNA><Deoxyribonucleic Acid><Dermal><Dermal injury><Development><Di-2-chloroethyl Sulfide><Dichlorodiethyl Sulfide><Differentiation and Growth><Doctor of Philosophy><Drug Delivery><Drug Delivery Systems><Drugs><Dysfunction><EC 2.3><Effectiveness><Endocannabinoids><Endogenous Cannabinoids><Enzyme Gene><Enzymes><Epidermis><Exposure to><FAAH inhibitor><FAAH protein><Formulation><Functional disorder><G-Proteins><GTP-Binding Proteins><GTP-Regulatory Proteins><Generations><Glycerol Monoester Hydrolases><Glycerol-ester acylhydrolase><Goals><Grant><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><HN-2><HN2><Healing abnormal><Healing delayed><Human><Human Resources><Impaired healing><Impaired tissue repair><Impaired wound healing><Inflammation><Inflammation Mediators><Inflammatory Response><Injury><Intracellular Communication and Signaling><Lead><Lecithinases><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Link><Lipid Peroxidation><Liquid substance><Manpower><Mechlorethamine><Mediating><Medication><Metabolic><Methods><Methylchlorethamine><Mice><Mice Mammals><Modern Man><Monoacylglycerol Lipases><Monoglyceride Esterases><Monoglyceride Hydrolase><Monoglyceride Lipases><Murine><Mus><Mustard><Mustard Gas><Mustine><N arachidonoyl 2 hydroxyethylamide><N-arachidonoylethanolamine><NSAIDs><Nitrogen Mustard><Non Steroidal Antiinflammatory Agents><Non-Steroidal Anti-Inflammatory Agents><Nonsteroidal Anti-Inflammatory Agents><Nonsteroidal Antiinflammatory Agents><Nonsteroidal Antiinflammatory Drug><Oxidative Stress><Oxygen Radicals><PPAR alpha><PPAR-α><PPARalpha><PPARα><Pb element><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor α><Ph.D.><PhD><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmaceutics><Pharmacy (field)><Pharmacy Schools><Phospholipase><Physiopathology><Play><Pro-Oxidants><Process><Protein Binding><Proteins><Public Health Schools><R-Series Research Projects><R01 Mechanism><R01 Program><Reactive Oxygen Species><Receptor Protein><Reporting><Research Grants><Research Project Grants><Research Projects><Role><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Skin injury><Structure><Sulfides><Sulfur Mustard><System><Testing><Tissues><Topical Drug Administration><Topical application><Toxic effect><Toxicities><Universities><Up-Regulation><Upregulation><Vesicants><Vesication><Wound Healing><Wound Repair><Wounds and Injuries><Yellow Cross Liquid><Yperite><abnormal tissue repair><anandamide><antiinflammatory><arachidonoyl ethanolamide><arachidonoylethanolamide><arachidonylethanolamide><associate faculty><associate professor><biological adaptation to stress><biological signal transduction><biosynthesis><bound protein><cannabinoid receptor><cannabinoid receptor 1><cannabinoid receptor 2><cannabinoid receptor type 1><cannabinoid receptor type 2><cell growth><chloromethine><cytotoxic><delayed wound healing><dermal exposure><develop therapy><developmental><drug development><drug/agent><eCB system><endocannabinoid system><endogenous cannabinoid system><ethylamine><fatty acid amide hydrolase><fatty acid amide hydrolase inhibitor><fluid><heavy metal Pb><heavy metal lead><improved><inflammation marker><inflammatory marker><inflammatory mediator><innovative technologies><intervention development><keratinocyte><lead optimization><liquid><mid-career faculty><midcareer faculty><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><non-steroidal anti-inflammatory drugs><non-steroidal antiinflammatory drugs><nonsteroidal anti-inflammatory drugs><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><oleamide hydrolase><pathophysiology><personnel><professor><protein crosslink><reaction; crisis><receptor><response><social role><stress response><stress; reaction><therapy development><topical administration><topical delivery><topical drug application><topical treatment><topically applied><treatment development>