Explant human skin perfusion model to study mechanisms of chemical injury and mitigation

The changing geopolitical environment has increased the risk of mass population exposure to chemical vesicants-induced skin injuries from a large-scale incident improvised by a state or terrorist organization executed act but there are few countermeasures available having limited efficacy. The long-term goal is to develop a potent therapy for the treatment of chemical vesicant-induced injuries and its addition to the national stockpile. The overall objectives of this proposal are to (i) equip our laboratory with trained human resources and facilities that enable us to conduct research in the area of chemical vesicant-countermeasures development and (ii) understand the dynamics and mechanism(s) of vesicants-induced skin injuries. The central hypothesis is that understanding the dynamics of human skin response and the mechanism of the response to chemical vesicants is the key to designing efficient countermeasures. The rationale for this project is that our novel human skin perfusion model offers a unique opportunity to test the dynamics and mechanism(s) of human skin injury to vesicants in a controlled environment. The central hypothesis will be tested by pursuing three specific aims: 1); Equip our laboratory and acquire essential training to handle toxic vesicants and human skin perfusion system. 2); Implement a human skin bioreactor workflow for rigorous evaluation of the effects of NM and PAO vesicants 3) Investigate the mechanism(s) of vesicant-induced cell injury and death pathways in human skin. Under the first aim, we will procure additional safety equipment and get the training to handle toxic vesicants and operate the human skin perfusion system. The second aim will focus to study the dynamics of vesicants-induced injury in response to different doses and exposure times. While the third aim is focused to determine the mechanism(s) of the injury. The proposal is innovative, as it aims to perform pre-clinical mechanistic studies using a novel platform in human tissues. The proposed research is significant because the successful completion of this project will provide a strong scientific platform for investigating targeted countermeasures strategies against vesicant-induced skin injuries and due to the use of the human tissue as a model the approval pathway of countermeasures for inclusion into the national stockpile can be accelerated.