Connor Tseng Rose Hills
Transcriptional Regulation of Autophagy in Macular Degeneration
Age-related macular degeneration (AMD) is the leading cause of blindness in older adults worldwide. The retinal pigment epithelium (RPE), a layer of the retina, is the primary site of injury in AMD. Photoreceptor outer segments are constantly being renewed, so the RPE degrades the older outer segment tips in order to maintain photoreceptor health and vision. Lipofuscin bisretinoids (undigested vitamin A metabolites) disrupt autophagy in the RPE, contributing to macular degeneration pathogenesis. Interestingly, outer segment degradation is unaffected in AMD, suggesting that the outer segment clearance is regulated by a mechanism other than autophagy. The Lakkaraju Lab suggests that autophagy gene expression is regulated by Forkhead Box (FOXO3), a distinct transcriptional program in the RPE. Since FOXO3 is not activated by the outer segment phagocytosis in the RPE, impaired activation of FOXO3 could contribute to autophagic defects in the RPE in AMD. I will investigate the role of FOXO3 in regulating autophagy and determine if FOXO3 activation is impaired in models of macular degeneration to establish whether FOXO3 is a therapeutic target for age-related diseases.