First Aid Medicine to Treat Vesicant Induced Corneal Injury

治疗疱疹引起的角膜损伤的急救药物

• 批准号: 10707316
• 负责人: Heather Chandler
• 金额: $ 78.18万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707316
• 关键词: Ablation; Acute; Advanced Development; Affect; Animal Model; Aqueous Humor; Benefits and Risks; Biology; Cell membrane; Cellular Structures; Chemicals; Contracts; Cornea; Corneal Injury; Cutaneous; Data; Dermal; Development; Dose; Environment; Epithelial Cells; Epithelium; Event; Eye; Eye Injuries; Eyedrops; Fibrosis; Film; First Aid; Goals; Goblet Cells; Homeostasis; Human; Immune response; In Vitro; Infiltration; Injury; Joints; Knowledge; Lesion; Manuscripts; Measures; Mechlorethamine; Medical; Medicine; Modeling; Mus; Mustard Gas; Nature; Ocular Pathology; Ohio; Organ; Oryctolagus cuniculus; Patients; Pharmacologic Substance; Phase; Photophobia; Physiology; Process; Production; Program Development; Protein Family; Proteins; Protocols documentation; Publishing; Reagent; Recombinants; Regenerative Medicine; Regenerative capacity; Regimen; Resistance; Respiratory System; Rodent; Role; Safety; Societies; Stress; Surface; Symptoms; TRIM Gene; Technology; Therapeutic; Topical application; Toxic effect; Toxicology; Transgenic Mice; Treatment Efficacy; Ulcer; United States National Institutes of Health; Universities; Vascularization; Vesicants; Wild Type Mouse; chemical threat; corneal epithelial stem cells; corneal epithelial wound healing; corneal epithelium; epithelium regeneration; extracellular; improved; in vivo; irritation; limbal; live cell imaging; member; novel; ocular surface; preservation; programs; pulmonary symptom; repaired; response to injury; screening program; stem cell function; stem cell survival; stem cells; therapeutic protein; tissue injury; tissue repair; validation studies; wound healing

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.

项目摘要 硫芥末（SM）和氮芥末（NM）是有效的化学威胁，会损害角膜， 包括急性恐惧症和角膜病变，随后流失了边缘干细胞（LSC）并延长 溃疡和血管化。针对急性和延长阶段的治疗方法 SM/NM毒性可以潜在地提供有效的措施来抵消角膜损伤。我们提供小说 支持组织修复蛋白MG53的益处，在治疗囊泡诱导的角膜伤口方面。 与野生型小鼠相比，mg53 - / - 同窝鼠显示出延迟的角膜重新上皮化，增加了 NM暴露后，LSC缺乏症的所有标志。更远， 持续升高MG53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MG53蛋白（RHMG53）可防止对LSC和角膜上皮细胞的损伤 在NM暴露期间保持角膜完整性。我们还知道MG53蛋白天然存在于眼泪中 电影和水性幽默，支持角膜稳态中MG53的生理学以及使用的安全性质 RHMG53治疗角膜损伤。该U01项目的目标是开发RHMG53作为潜在的有效蛋白质 治疗性可减轻囊泡角膜损伤的急性和延长阶段。我们将为RHMG53制定 眼科应用是一种急救药物，可以作为医疗储备库存并迅速部署到 发生化学威胁时会影响患者。将进行体外和离体研究以阐明 MG53在防止NM引起的LSC和角膜上皮损伤方面的机械作用。验证 研究将在vesicant引起的角膜损伤的小鼠和兔模型中对RHMG53进行研究 确定RHMG53在拯救角膜功能中的治疗功效和安全窗口。总体而言，这个U01 计划提供了一个独特的机会，将MG53的生物学推向了重要的抵消治疗。