First Aid Medicine to Treat Vesicant Induced Corneal Injury

项目摘要 硫磺芥末(SM)和氮芥末(NM)是对角膜造成损害的潜在化学威胁， 包括急性畏光和角膜病变，随后是角膜缘干细胞(LSCs)的丧失和延长 溃疡和血管化。针对急性期和延长期的治疗方法 SM/NM的毒性可能提供有效的措施来对抗角膜损伤。我们提供新奇的 这些发现支持组织修复蛋白MG53在治疗起泡剂引起的角膜伤口方面的好处。 与野生型小鼠相比，MG53-/-小鼠表现出角膜再上皮化延迟，增加 NM暴露后的血管形成和结膜形成，这些都是LSC缺乏的特征。此外， MG53持续升高的转基因小鼠对NM诱导的角膜损伤具有抵抗力。我们发现， 重组人MG53蛋白对LSCs和角膜上皮细胞损伤的保护作用 在近视照射期间保持角膜的完整性。我们还知道MG53蛋白天然存在于泪水中 膜和房水，支持MG53在角膜动态平衡中的生理学和使用的安全性 RhMG53用于治疗角膜损伤。该U01项目的目标是开发出一种潜在的有效蛋白--重组人MG53 治疗以减轻起泡性角膜损伤的急性期和延长期。我们将为以下目标制定rhMG53 作为急救药物的眼科应用，可以作为医疗储备储存并迅速部署到 在受到化学威胁的情况下受影响的患者。将进行体外和体外研究，以阐明 MG53对NM诱导的LSCs和角膜上皮损伤的保护作用验证 将用重组人MG53在小鼠和兔的发泡剂诱导的角膜损伤模型上进行研究，以 确定rhMG53挽救角膜功能的疗效和安全窗。总体而言，这款U01 该计划提供了一个独特的机会，将MG53的生物学发展成为一种重要的中和疗法。

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.