Targeting Citrullination in Ocular Chemical Injury

摘要： 为战争开发的化学武器武器库继续是国土安全 威胁，因为这些特工可以被部署来造成大规模伤亡。发泡剂，如 硫磺芥末和氮芥末对受影响的眼睛和肺造成严重的急性损伤 由于纤维性疤痕而对视力造成严重长期后果的组织。因此，治疗 因为这种伤害是具有挑战性的，因为它们的部署方式将有利于 在类似战场的非理想条件下快速批量投放。暴露于硫磺芥末 也会影响人类的视网膜内部组织，因此必须考虑到 整只眼睛都处于危险之中。严重的眼睛损伤对角膜和视网膜也会发生在 暴露在氢氧化钠中，这是一种已经被很好研究的腐蚀剂。因此，人们可以 重新调整碱损伤的病理生物学并预测可能的靶点和途径 参与了由芥菜造成的伤害。通过对碱损伤的调查，我们发现 这种化学物质会显著增加视网膜胶质细胞增生症和高瓜氨酸血症。 瓜氨酸化是一种翻译后修饰，与许多纤维化疾病有关。我们 研究表明，高瓜氨酸化是由肽基精氨酸脱亚胺酶(PAD)-4的表达驱动的。 我们展示了PAD4在创伤后治疗范例中是可用药的 抑制会有效地阻断高瓜氨酸化。因此，在这份R21拨款提案中， NIH中和计划，我们计划研究氮芥菜中的瓜氨酸化途径 采用小鼠和兔角膜损伤模型。我们的计划是证明 高瓜氨酸化是氮芥损伤的重要病理过程，检测 假设PAD4是蛋白质瓜氨酸化的主要驱动因素。因此，我们计划同时使用一个 小分子抑制剂和PAD4基因缺陷范例有助于验证这一可药物 目标。我们的最终目标是阐明新的可用药靶点，并解开一种治疗方法 将有助于发展未来药物开发合作的范例，并与 反制程序。

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.