Targeting Citrullination in Ocular Chemical Injury

针对眼部化学损伤的瓜氨酸化

• 批准号: 10705952
• 负责人: ROYCE MOHAN
• 金额: $ 9.31万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705952
• 关键词: Achievement; Acute; Affect; Alkalies; Animal Model; Anterior; Applications Grants; Arginine deiminase; Attenuated; Automobile Driving; Burn injury; Caustics; Cell Culture Techniques; Chemical Injury; Chemical Weapons; Chemicals; Chronic; Cicatrix; Clinic; Clinical; Collaborations; Contracts; Cornea; Corneal Injury; Data; Development; Disease; Down-Regulation; Drug Modelings; Enzymes; Exposure to; Eye; Eye Injuries; Fibrosis; Foundations; Future; Genetic; Glial Fibrillary Acidic Protein; Gliosis; Goals; Human; Incidence; Infection prevention; Inflammation; Injury; Intermediate Filaments; Isoenzymes; Knowledge; Laboratories; Lead; Link; Lung; Measures; Mechlorethamine; Medical; Modeling; Molecular; Morbidity - disease rate; Muller' s cell; Mus; Mustard; Mustard Gas; Organ Culture Techniques; Organ failure; Oryctolagus cuniculus; Outcome; Pain; Pathologic Processes; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Poison; Population; Post-Translational Protein Processing; Process; Protein Isoforms; Proteins; Retina; Risk; Role; Security; Skin; Sodium Hydroxide; Structure of parenchyma of lung; Sulfur; Terrorism; Testing; Therapeutic; Time; Tissues; Topical application; Translating; Ulcer; United States National Institutes of Health; Up-Regulation; Validation; Vesicants; Vimentin; Vision; Work; acute toxicity; analog; cellular targeting; chemical disaster; citrullinated protein; corneal scar; drug development; drug efficacy; druggable target; healing; in vivo; inhibitor; injured; injury and repair; mass casualty; medical countermeasure; mouse model; new therapeutic target; overexpression; programs; repaired; response to injury; small molecule inhibitor; soft tissue; symptom management; wound healing

Abstract: The arsenal of chemical weapons developed for warfare continues to be a homeland security threat, as these agents can be deployed to cause mass casualty. Vesicant agents, such as sulfur mustard and nitrogen mustard cause severe acute injury in the affected ocular and lung tissues with serious long-term consequences on vision due to fibrotic scarring. Thus, treatments for such injuries are challenging, because they will have to be deployed in manner conducive for rapid mass delivery under non-ideal conditions similar to battlefields. Exposure to sulfur mustard also affects the internal retinal tissues in humans, and hence, consideration must be taken that the whole eye is at risk. Serious eye injury to both the cornea and retina also occurs from exposure to sodium hydroxide, a caustic agent that has been well studied. Thus, one could repurpose the pathobiology of alkali injury and predict targets and pathways that would likely be engaged in injuries produced by the mustards. Investigating alkali injury, we have unraveled that this chemical causes potent increase in retinal gliosis and hypercitrullination acutely. Citrullination is a posttranslational modification that is linked to a number of fibrotic diseases. We showed that hypercitrullination is driven by expression of peptidyl arginine deiminase (PAD)-4. Demonstrating that PAD4 is druggable in a post injury treatment paradigm, we showed PAD4 inhibition results in potent blockade of hypercitrullination. Thus, in this R21 grant proposal to the NIH CounterACT program, we plan to examine the citrullination pathway in nitrogen mustard injury employing mouse and rabbit corneal injury models. Our plan is to demonstrate that hypercitrullination is an important pathological process in nitrogen mustard injury and test the hypothesis that PAD4 is the principal driver of protein citrullination. Hence, we plan to use both a small molecule inhibitor and PAD4-genetic deficiency paradigms to help validate this druggable target. Our ultimate goal is to illuminate novel druggable targets and unravel a treatment paradigm that will help develop future collaborations for drug development and aligned with the CounterACT program.

抽象的： 为战争开发的化学武器的武器库仍然是国土安全 威胁，因为可以部署这些代理商来造成大规模伤亡。囊泡剂，例如 硫芥末酱和氮芥末在受影响的眼和肺中造成严重的急性损伤 由于纤维化疤痕而对视力产生严重后果的组织。因此，治疗 因为这种伤害具有挑战性，因为它们必须以有利于的方式部署 在非理想条件下类似于战场的非理想条件下的质量迅速交付。暴露于硫芥末 还会影响人类内部视网膜组织，因此必须考虑考虑 整个眼睛都有风险。角膜和视网膜的严重眼睛受伤也发生 暴露于氢氧化钠，这是一种苛性剂，已经进行了很好的研究。因此，可以 重新利用碱损伤的病理生物学，并预测可能是可能是的靶标和途径 从事芥末造成的伤害。调查碱性损伤，我们已经解开了 该化学物质会急性增加视网膜神经胶质病和过度乳腺癌。 柠檬化是一种翻译后修饰，与多种纤维化疾病有关。我们 表明高硝化作用是由肽基精氨酸脱氨酶（PAD）-4的表达驱动的。 证明PAD4在受伤后治疗范式中是可毒品的，我们显示了PAD4 抑制作用导致过度乳腺癌的有效封锁。因此，在此R21赠款提案中 NIH抵抗计划，我们计划检查氮芥末中的柠檬化途径 使用小鼠和兔角膜损伤模型的伤害。我们的计划是证明 高硝基化是氮芥末损伤中的重要病理过程，并测试 假设PAD4是蛋白质柠檬酸的主要驱动力。因此，我们计划同时使用 小分子抑制剂和PAD4基因缺乏范式，以帮助验证这种可药的 目标。我们的最终目标是阐明新颖的可毒靶标并解散治疗 将有助于发展药物开发的未来合作，并与 抵消程序。

项目成果

Peptidyl arginine deiminase 4 deficiency protects against subretinal fibrosis by inhibiting Müller glial hypercitrullination.

• DOI: 10.1002/jnr.25158
• 发表时间: 2023-04
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Palko, Sarah I.;Saba, Nicholas J.;Bargagna-Mohan, Paola;Mohan, Royce
• 通讯作者: Mohan, Royce

A corneo-retinal hypercitrullination axis underlies ocular injury to nitrogen mustard.

• DOI: 10.1016/j.exer.2023.109485
• 发表时间: 2023-04
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: E. Umejiego;Ricky Paramo;Alexander Zafiris;Elias M. Mullane;P. Bargagna-mohan;R. Mohan