Development of a protein therapeutics to counteract mustard-induced skin injury

点击翻译按钮获取中文摘要

PROJECT SUMMARY Sulfur mustard (SM) and nitrogen mustard (NM) are vesicant agents that cause blistering of the skin. As alkylating agents, SM/NM causes skin injuries through complicated cellular events, involving DNA damage, free radical formation, and lipid peroxidation. Development of therapeutic approaches that target the multi-cellular process of tissue injury-repair can potentially provide effective countermeasures to combat vesicant-induced dermal lesions. Our group previously identified MG53 as an essential component of cell membrane repair. Compared with the wild type mice, the mg53-/- mice show increased susceptibility to NM-induced dermal injuries, whereas transgenic mice with overexpression of MG53 are resistant to dermal exposure of NM. Using live-cell imaging, we made an unexpected and potentially exciting finding that in human follicle stem cells (HFSCs) treated with NM, the intrinsic membrane repair function of MG53 was compromised. However, the application of exogenous recombinant human MG53 (rhMG53) protein could restore cell membrane integrity from NM-induced injury in both keratinocytes and HFSCs. We have generated preliminary data to show that topical administration of rhMG53 can mitigate NM-induced dermal injury in mice. Studies proposed in this Exploratory and Developmental R21 project are focused on understanding the mechanistic action of MG53 in skin wound repair following NM exposure (Aim 1), and establishing the efficacious dose and effective time window for rhMG53 application to treat NM-induced skin injuries in mice (Aim 2). Pending on positive findings from this R21 project, we plan to submit a larger CounterACT U01 application to further build the proof-of-concept data in large animal models of SM-induced cutaneous injury, and to seek partnership with FDA and BARDA for advancing rhMG53 as a novel protein therapeutic that can be stockpiled as a medical reserve to treat cutaneous (and other organs) injuries in the event of chemical warfare.