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While the abundance of MCs in the choroid implies their fundamental importance in the eye, little is known about the significance of MCs and their degranulation in choroid. The cause of geographic atrophy (GA), a progressive dry form of age\u2010related macular degeneration is elusive and there is currently no therapy for this blinding disorder. Here we demonstrate in both human GA and a rat model for GA, that MC degranulation and MC\u2010derived tryptase are central to disease progression. Retinal pigment epithelium degeneration followed by retinal and choroidal thinning, characteristic phenotypes of GA, were driven by continuous choroidal MC stimulation and activation in a slow release fashion in the rat. Genetic manipulation of MCs, pharmacological intervention targeting MC degranulation with ketotifen fumarate or inhibition of MC\u2010derived tryptase with APC 366 prevented all of GA\u2010like phenotypes following MC degranulation in the rat model. Our results demonstrate the fundamental role of choroidal MC involvement in GA disease etiology, and will provide new opportunities for understanding GA pathology and identifying novel therapies targeting MCs.<\/jats:p>","DOI":"10.1096\/fj.202000807r","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T14:16:16Z","timestamp":1596032176000},"page":"10117-10131","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["A role for mast cells in geographic atrophy"],"prefix":"10.1096","volume":"34","author":[{"given":"Shuntaro","family":"Ogura","sequence":"first","affiliation":[{"name":"Wilmer Ophthalmological Institute Johns Hopkins Hospital Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajkumar","family":"Baldeosingh","sequence":"additional","affiliation":[{"name":"Wilmer Ophthalmological Institute Johns Hopkins Hospital Baltimore MD 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