Developing Treatment Paradigms for Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is one of the leading causes of blindness among the elderly affecting over 30 million individuals world-wide. AMD initiates in the back of the eye because of dysfunctions in the retinal pigment epithelium (RPE), a monolayer of cells that maintains vision through maintenance of photoreceptor healthy and integrity. AMD can lead to severe vision loss and blindness in advanced stages – “dry” and “wet” forms. In the dry stage, the death of RPE cells triggers photoreceptor cell death and atrophy of the choroidal blood supply causing vision loss. It is thought that RPE cell death in AMD is triggered by the formation of sub-RPE protein/lipid deposits called drusen. Our recent work shows that drusen formation is initiated by reduced autophagic flux in RPE cells resulting in reduced ability of RPE cells to process intracellular “debris” that eventually gets secreted as drusen deposits. TFEB, a member of MiT family of transcription factors is a known master regulator of autophagy. Here, we propose to investigate the activity of transcription factor TEFB in our AMD cellular models of iPSC-derived RPE cells. We hypothesize that autophagy downregulation is triggered by post-translational changes in TFEB that affect its sub-cellular localization and reduce its transcriptional activity. Here, we propose to identify those changes in TEFB and discover signaling pathways that lead to its altered activity. Lastly, we will test the ability of our recently discovered FDA-approved drugs that stimulate TEFB activity to reduce drusen formation by increasing autophagy in iPSC-RPE AMD models. This work will lead to a better understanding of AMD pathogenesis and potentially retool existing  drugs to treat AMD patients.