The cause of geographic atrophy (GA), a progressive dry form of age-related macular degeneration (AMD), is elusive and there is currently no therapy for this blinding disorder. Our prior studies have demonstrated that RPE death is accompanied by attenuation of choriocapillaris (CC). Like other tissues in the aging body, the choroid is undergoing low grade chronic inflammation, termed inflammaging. This is logical because, in the GA choroid, there is elevated complement C3a and 5a, as well as advanced glycosylation end products, and C- reactive protein (CRP). CRP is an acute phase reactant and an active regulator of the innate immune system that has been suggested by some to be a risk factor for AMD. There are also two resident inflammatory cells in choroid, mast cells (MCs) and macrophages. We have previously demonstrated that macrophages are activated in GA and MC numbers and the number of degranulated MCs are increased in GA choroid. Our recent study demonstrated that simply degranulating MCs with slow-released 48/80 (a snake-venom like compound) causes a GA-like phenotype: degeneration of RPE, visual function decline, and thinning of retina and choroid. In a pilot study, we observed that slow- released subconjunctival CRP stimulated MC degranulation in rat choroid and RPE degeneration. In the proposed studies, we investigate the effect of CRP at a physiologically relevant level on the RPE/Bruchs membrane/CC complex in vitro and in our in vivo rat model. The proposed studies will determine if CRP, which is greatly elevated in AMD choroid, acts directly on RPE or whether its effect is via activation of macrophages and/or mast cells. All three cells express Fcγ receptors, which are some of CRP binding sites. If MC degranulation is the cause of RPE degeneration, we will determine if MC granules or exosomes are responsible. The RPE migration at the border of GA atrophy is presumed to be epithelial to mesenchyme transition (EMT) but this has not been characterized and the cause of this event is unknown. We will first determine if this is EMT in human GA and in our rat model. Then we will investigate in vitro if CRP stimulates EMT directly or if CRP-induced MC degranulation is the cause. Our results will provide new opportunities for understanding GA pathology and determine the role that choroidal CRP plays in GA. Our studies also have the potential of identifying novel therapies for GA by quiescing MCs or by preventing CRP from binding its FCγ receptors.