First Aid Medicine to Treat Vesicant Induced Corneal Injury

项目摘要 硫芥（SM）和氮芥（NM）是对角膜造成损害的强效化学威胁， 包括急性角膜恐惧症和角膜病变，随后是角膜缘干细胞（LSC）的丧失和长期的 溃疡和血管形成。针对急性期和长期期的治疗方法 SM/NM毒性可能提供对抗角膜损伤的有效措施。我们提供新颖的 研究结果支持MG 53（一种组织修复蛋白）在治疗发泡剂诱导的角膜伤口中的益处。 与野生型小鼠相比，同窝出生的mg 53-/-小鼠的角膜上皮再生延迟， NM暴露后的血管化和结膜化，都是LSC缺乏的标志。此外，本发明还 MG 53持续升高的转基因小鼠对NM诱导的角膜损伤具有抗性。我们发现 重组人MG 53蛋白（rhMG 53）保护LSC和角膜上皮细胞免受损伤， 在NM暴露期间保持角膜完整性。我们还知道MG 53蛋白天然存在于泪液中， 膜和房水，支持MG 53在角膜稳态中的生理学和使用的安全性 rhMG 53治疗角膜损伤。本U 01项目的目标是开发rhMG 53作为潜在的有效蛋白 治疗缓解急性期和长期期的水疱性角膜损伤。我们将配制rhMG 53用于 作为急救药物的眼部应用，可以作为医疗储备储存并迅速部署， 在化学威胁事件中受影响的患者。将进行体外和离体研究以阐明 MG 53在保护LSC和角膜上皮免受NM诱导的损伤中的机制作用。验证 将用rhMG 53在发泡剂诱导的角膜损伤的小鼠和兔模型中进行研究， 确定rhMG 53挽救角膜功能的疗效和安全窗。总体而言，U 01 该计划提供了一个独特的机会，将MG 53的生物学推进到一个重要的对抗治疗。

Project Summary Sulfur mustard (SM) and nitrogen mustard (NM) are potent chemical threats that cause damage to the cornea, including acute photophobia and corneal lesions followed by loss of limbal stem cells (LSCs) and prolonged ulceration and vascularization. Therapeutic approaches targeting both the acute and prolonged phases of SM/NM toxicity can potentially provide effective measures to counteract corneal injuries. We provide novel findings that support the benefits of MG53, a tissue repair protein, in treating vesicant-induced corneal wounds. Compared with wild type mice, mg53-/- littermates show delayed corneal re-epithelialization, increased vascularization and conjunctivatization following NM exposure, all hallmarks of LSC deficiency. Further, transgenic mice with sustained elevation of MG53 are resistant to NM-induced corneal injury. We find that the recombinant human MG53 protein (rhMG53) protects against injury to LSCs and corneal epithelial cells to preserve cornea integrity during NM exposure. We also know that MG53 protein is naturally present in the tear film and aqueous humor, supporting the physiology of MG53 in corneal homeostasis and the safe nature of using rhMG53 to treat corneal injuries. The goal of this U01 project is to develop rhMG53 as a potential effective protein therapeutic to mitigate the acute and prolonged phases of vesicant corneal injury. We will formulate rhMG53 for ocular application as a first-aid medicine that can be stockpiled as a medical reserve and rapidly deployed to affected patients in the event of chemical threats. In vitro and ex vivo studies will be performed to elucidate the mechanistic action of MG53 in protecting against NM-induced injury to LSCs and corneal epithelia. Validation studies will be conducted with rhMG53 in mouse and rabbit models of vesicant-induced corneal injuries to determine the therapeutic efficacy and safety windows of rhMG53 in rescuing cornea function. Overall, this U01 program provides a unique opportunity to advance the biology of MG53 into an important counteract therapeutic.