Molecular Mechanisms that Regulate Cellular Clearance Functions in the RPE
We used novel approaches to study the cellular impact of induction of TFEB, a master cellular regulator of autophagy and lysosomal function. These strategies are expected to enhance the clearance of undigested cellular material in the RPE. We propose to 1). Use an adeno-associated viral vector (AAV)-mediated delivery of constitutively active TFEB to the RPE, and 2). Use of oligonucleotides that inhibit microRNA-binding to TFEB. These studies are expected to establish a strategy for sustained activation of TFEB expression in the RPE. Restoring lysosomal function and autophagy in RPE cells can be effective in preventing RPE cell dysfunction in the pathogenesis of Age-related Macular Degeneration (AMD). In order to achieve this, it is imperative to understand the mechanisms regulating autophagy and lysosomal function in the RPE, and our knowledge in this regard is limited. This project aims to identify molecular mechanisms regulating autophagy and lysosomal function and to use this knowledge to develop effective therapeutic strategies to inhibit the loss of RPE cells in AMD.