Targeting Citrullination in Ocular Chemical Injury

摘要： 为战争而开发的化学武器库继续成为国土安全 威胁，因为这些代理人可以部署造成大规模伤亡。发泡剂，例如 硫芥子气和氮芥子气会对受影响的眼睛和肺部造成严重的急性损伤 由于纤维化瘢痕形成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，因为他们必须以有利于 在类似于战场的非理想条件下快速大规模输送。接触硫芥子气 也影响人类的内部视网膜组织，因此，必须考虑到， 整只眼睛都有危险角膜和视网膜的严重眼损伤也发生在 暴露于氢氧化钠，一种已经被充分研究的腐蚀剂。因此，可以 重新利用碱损伤的病理生物学，并预测可能发生的靶点和途径。 参与芥末造成的伤害。通过调查碱伤，我们发现 这种化学物质会导致视网膜神经胶质增生和瓜氨酸过多的急剧增加。 瓜氨酸是一种翻译后修饰，与许多纤维化疾病有关。我们 表明高瓜氨酸血症是由肽基精氨酸脱亚胺酶（PAD）-4的表达驱动的。 为了证明PAD 4在损伤后治疗范例中是可药物化的，我们展示了PAD 4 抑制导致高瓜氨酸的有效阻断。因此，在这个R21赠款提案中， NIH CounterACT计划，我们计划检查氮芥中的瓜氨酸途径 使用小鼠和兔角膜损伤模型。我们的计划是证明 高瓜氨酸血症是氮芥损伤的重要病理过程， 假设PAD 4是瓜氨酸蛋白的主要驱动因子。因此，我们计划同时使用 小分子抑制剂和PAD 4-遗传缺陷范例，以帮助验证这种药物 目标我们的最终目标是阐明新的药物靶点， 范式，这将有助于开发未来的药物开发合作，并与 CounterACT计划。

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.