SUMMARY: Death of the choroid, the vascular bed underlying the retina, is a prominent pathologic hallmark of numerous inherited retinal degenerative diseases as well as age-related macular degeneration (AMD). Choroidal death is likely impacted by dysfunction of the retinal pigment epithelium (RPE), a monolayer of cells between the photoreceptors and the choroid. A critical knowledge gap impeding progress in therapeutic strategies is how RPE dysfunction contributes to choroidal death. Choroideremia is an inherited chorioretinal degeneration leading to early blindness with no current treatment. Several lines of evidence implicate the RPE as the primary site of degeneration, with secondary degeneration of the photoreceptors and choroid. The causative genetic defect is deficiency of CHM, encoding Rab escort protein 1 (REP-1), which facilitates prenylation of Rab GTPases, a critical step in membrane trafficking. RPE cells are highly polarized and differentially secrete numerous growth factors and signaling molecules in a directional manner towards the photoreceptors and choroid. The proposed studies will elucidate how RPE membrane trafficking defects in choroideremia alter protein secretion and how this impacts choroidal survival. The long-term goal of this work is to develop the necessary skills and expertise to establish an independent career focused on therapies targeting RPE dysfunction in retinal degenerative disease. The scientific objective is to understand mechanisms of choroidal death. We will test the hypothesis that alterations in RPE secretion of proteins in the vascular survival pathway lead to choroidal atrophy in choroideremia using a human stem cell derived RPE model. The career development objectives are to master stem cell culture and RPE derivation techniques, to develop expertise in membrane trafficking pathways of RPE, to become proficient in the techniques and principles of therapeutic target discovery, and to develop skills in leadership, mentorship, and scientific communication necessary to become a successful independent investigator. The proposed study will increase the candidate’s understanding of choroideremia and identify therapeutic targets in this untreatable blinding disease, which may also have broader implications for choroidal degeneration in AMD and other chorioretinal degenerative diseases.