Targeting Citrullination in Ocular Chemical Injury

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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.