Abstract This is an application to the Countermeasures Against Chemical Threats (CounterACT) NIH-wide program part of the Chemical Countermeasures Research Program. Sulfur mustard (SM), a chemical warfare agent, and nitrogen mustard (NM), a chemotherapeutic agent, are both potent vesicants. The cornea is exquisitely sensitive to these agents leading to keratitis, vascularization, ulceration, and perforations. Following acute SM exposure, a subset of patients will experience chronic/delayed-onset ocular complications known as mustard gas keratopathy (MGK). Delayed MGK reportedly can manifest several years after the initial exposure and presents with severe corneal disease with significant visual loss. We have made the observation that in experimental animal models of NM injury to the cornea, there is dose-dependent increased senescence in the cornea. We hypothesize that senescence in the cornea promotes tissue dysfunction and inflammationand that senescence after mustard injury contributes to the progression of chronic MGK and the severity of delayed MGK. We further hypothesize that reducing/eliminating senescent cells may alter the progression and severity of MGK. In this application we propose in Aim1 to investigate the role of senescence and SASP in the progression of corneal disease following acute exposure to NM; and in Aim 2 to investigate the role of senescence in a new model of delayed MGK. At the conclusion of these studies, we expect to have an improved understanding of the role of senescence in the development of MGK and identify novel approaches for its prevention/treatment.