UMDNJ/Rutgers University CounterACT Research Center of Excellence

描述(由申请人提供)：这是UMDNJ/罗格斯大学对抗卓越研究中心的续签申请，该中心专门致力于发现和开发治疗因接触发泡剂而中毒的药物，包括硫芥末、氮芥末和其他机械相关的化学威胁剂。该中心由三个研究和开发项目组成，每个项目都专注于一个主要的发泡目标：眼睛、肺和皮肤。研究的中心是阐明发泡剂毒性的具体机制，总的目标是确定治疗干预的目标。这些项目得到了一个药理学和药物开发核心以及一个药物化学和制药核心的支持，该核心由在药物发现、交付和开发方面具有相当专业知识的研究人员组成。已经确定了重要的先导化合物，并开发了提高药理活性和改善药代动力学特征的创新配方和给药系统。超过150种潜在的治疗化合物被合成、配制，并在体外和抗发泡剂诱导的损伤中进行疗效评估，产生了四个不同的家族，这些家族将在更新期内进行化学优化。针对反对抗调查员大学的学生、博士后研究员和卫生保健提供者设立了一个培训和教育方案。在下一个赠款期间，机制研究将集中在与发泡剂如何损害组织有关的新发现上，包括自噬、基质金属蛋白酶、内质网应激蛋白和巨噬细胞亚群的作用。药理学和药物开发核心将继续与FDA举行非正式会议，进行支持IND的研究，协调与外部合作者的活动；它还将评估和推进选定的先导化合物。药物化学和药剂学核心将在化学上优化四个有前景的类别的先导化合物，并开发战略和靶向递送系统，以支持发泡剂介导的伤口愈合的多药剂/多机制治疗制度。预计中心的努力将导致新药进入审批程序，用于治疗人类发泡剂中毒。

DESCRIPTION (provided by applicant): 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.