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.
There is increasing concern that civilian populations might be exposed to chemical toxicants. The primary objective of the Center will be to develop medical countermeasures against these chemicals. A team of researchers has been assembled capable of rapid advancement of candidate drugs through the regulatory process, so that they can be used to enhance the medical response capabilities of the United States.
|Moretti, Alysha; Li, Qi; Chmielowski, Rebecca et al. (2018) Nanotherapeutics Containing Lithocholic Acid-Based Amphiphilic Scorpion-Like Macromolecules Reduce In Vitro Inflammation in Macrophages: Implications for Atherosclerosis. Nanomaterials (Basel) 8:|
|Szilagyi, John T; Fussell, Karma C; Wang, Yun et al. (2018) Quinone and nitrofurantoin redox cycling by recombinant cytochrome b5 reductase. Toxicol Appl Pharmacol 359:102-107|
|Joseph, Laurie B; Composto, Gabriella M; Perez, Roberto M et al. (2018) Sulfur mustard induced mast cell degranulation in mouse skin is inhibited by a novel anti-inflammatory and anticholinergic bifunctional prodrug. Toxicol Lett 293:77-81|
|Chang, Yoke-Chen; Gordon, Marion K; Gerecke, Donald R (2018) Expression of Laminin 332 in Vesicant Skin Injury and Wound Repair. Clin Dermatol (Wilmington) 2:|
|Malaviya, Rama; Laskin, Jeffrey D; Laskin, Debra L (2017) Anti-TNF? therapy in inflammatory lung diseases. Pharmacol Ther 180:90-98|
|Faig, Jonathan J; Moretti, Alysha; Joseph, Laurie B et al. (2017) Biodegradable Kojic Acid-Based Polymers: Controlled Delivery of Bioactives for Melanogenesis Inhibition. Biomacromolecules 18:363-373|
|Sunil, Vasanthi R; Vayas, Kinal N; Fang, Mingzhu et al. (2017) World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung. Exp Mol Pathol 102:50-58|
|Yang, Shaojun; Jan, Yi-Hua; Mishin, Vladimir et al. (2017) Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells. Chem Res Toxicol 30:1406-1418|
|Venosa, Alessandro; Gow, James G; Hall, LeRoy et al. (2017) Regulation of Nitrogen Mustard-Induced Lung Macrophage Activation by Valproic Acid, a Histone Deacetylase Inhibitor. Toxicol Sci 157:222-234|
|Francis, Mary; Sun, Richard; Cervelli, Jessica A et al. (2017) Editor's Highlight: Role of Spleen-Derived Macrophages in Ozone-Induced Lung Inflammation and Injury. Toxicol Sci 155:182-195|
Showing the most recent 10 out of 145 publications