This is a renewal application for the UMDNJ/Rutgers University CounterACT Research Center of Excellence, which is specifically focused on the discovery and development of drugs to treat poisoning from exposure to vesicants including sulfur mustard, nitrogen mustard, and other mechanistically related chemical threat agents. The Center consists of three Research and Development Projects, each focused on a major vesicant target: the eye, lung and skin. Research is centered on elucidating specific mechanisms of vesicant toxicity, with the overall goal of identifying targets for therapeutic intervention. These projects are supported by a Pharmacology and Drug Development Core and a Medicinal Chemistry and Pharmaceutics Core consisting of investigators with considerable expertise in drug discovery, delivery and development. Important lead compounds have been identified and innovative formulations and delivery systems developed that increase pharmacological activity and improve pharmacokinetic profiles. Over 150 potential therapeutic compounds were synthesized, formulated, and evaluated for efficacy in vitro and against vesicant-induced injury resulting in four distinct families that will be chemically optimized during the renewal period. A Training and Education Program has been established directed at students, postdoctoral fellows and health care providers at the Universities of CounterACT investigators. During the next grant period, mechanistic research will focus on following novel discoveries related to how vesicants damage tissues including studies on autophagy, matrix metalloproteinases, ER stress proteins, and the role of macrophage subpopulations. The Pharmacology and Drug Development Core will continue to have informal meetings with the FDA, conduct IND-enabling studies, coordinate activities with external collaborators; it will also evaluate and advance selected lead compounds. The Medicinal Chemistry and Pharmaceutics Core will chemically optimize lead compounds in four promising classes, as well as develop strategies and targeted delivery systems to support multiple agent/ multiple mechanism treatment regimes for vesicant-mediated wound healing. It is anticipated that Center efforts will result in new drugs that will be in the approval process for treating vesicant poisoning in humans.