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

开发蛋白质疗法来对抗芥末引起的皮肤损伤

• 批准号: 10667433
• 负责人: Haichang Li
• 金额: $ 19.69万
• 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: 2022-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667433
• 关键词: Ablation; Alkylating Agents; Animal Model; Blood Circulation; Bulla; Cell membrane; Cells; Cellular Membrane; Cellular Structures; Cessation of life; Chemical Warfare; Chemistry; Chronic; Clinical Research; Cream; Cutaneous; DNA Damage; Data; Dermal; Development; Dose; Epidermis; Event; Exposure to; Formulation; Free Radical Formation; Future; Genes; Hair follicle structure; Histologic; Human; Immobilization; Impairment; Inflammation; Injury; Intramuscular; Knowledge; Lesion; Link; Lipid Peroxidation; Longevity; Mechlorethamine; Medical; Membrane; Movement; Multicellular Process; Mus; Mustard; Mustard Gas; Organ; Oxidative Stress; Oxidative Stress Induction; Pathology; Penetration; Pilot Projects; Play; Predisposition; Process; Proteins; Reagent; Recombinants; Regenerative capacity; Rejuvenation; Research Personnel; Resistance; Role; Site; Skin; Skin injury; Therapeutic; Time; Tissues; Topical application; Toxic effect; Transgenic Mice; Ulcer; Vesicants; Wild Type Mouse; combat; dermal exposure; healing; injury and repair; keratinocyte; lipophilicity; live cell imaging; manufacture; manufacturing scale-up; mouse model; novel; novel therapeutics; overexpression; pre-clinical; preservation; prototype; repair function; repaired; skin wound; stem cell function; stem cells; success; therapeutic development; therapeutic protein; tissue injury; wound healing

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.

项目摘要 硫芥末酱（SM）和氮芥末（NM）是导致皮肤起泡的囊泡剂。作为 烷基化剂，SM/NM通过复杂的细胞事件造成皮肤损伤，涉及DNA损伤，游离 自由基形成和脂质过氧化。开发针对多细胞的治疗方法 组织损伤修复过程可能会提供有效的对策，以对抗囊泡诱导的 真皮病变。我们的小组先前将MG53鉴定为细胞膜修复的重要组成部分。 与野生型小鼠相比，Mg53 - / - 小鼠显示出对NM诱导的皮肤损伤的敏感性， 而Mg53过表达的转基因小鼠对NM的真皮暴露具有抗性。使用活细胞 成像，我们做出了一个意想不到且可能令人兴奋的发现，即在人卵泡干细胞（HFSC）中 用NM处理，MG53的固有膜修复功能受到损害。但是，应用 外源重组人MG53（RHMG53）蛋白可以恢复NM诱导的细胞膜完整性 角质形成细胞和HFSC的损伤。我们已经生成了初步数据，以表明局部管理 RHMG53的作用可以减轻小鼠NM诱导的皮肤损伤。在此探索性和 发育R21项目的重点是了解MG53在皮肤伤口修复中的机械作用 在NM暴露后（AIM 1），并确定RHMG53的有效剂量和有效的时间窗口 用于治疗小鼠NM诱导的皮肤损伤的应用（AIM 2）。等待这个R21项目的积极发现， 我们计划提交较大的抵消U01申请，以进一步构建大动物的概念验证数据 SM诱导皮肤伤害的模型，并与FDA和Barda寻求促进RHMG53的合作伙伴关系 作为一种新型的蛋白质治疗，可以作为治疗皮肤（和其他器官）的医疗储备库存 如果发生化学战，受伤。

项目成果

Sustained delivery of rhMG53 promotes diabetic wound healing and hair follicle development.

• DOI: 10.1016/j.bioactmat.2022.03.017
• 发表时间: 2022-12
• 期刊: Bioactive materials
• 影响因子: 18.9
• 作者: Niu H;Li H;Guan Y;Zhou X;Li Z;Zhao SL;Chen P;Tan T;Zhu H;Bergdall V;Xu X;Ma J;Guan J
• 通讯作者: Guan J