Attributions

Molecular Mechanisms that Regulate Cellular Clearance Functions in the RPE

Mallika Vlapala, PhD Indiana University

Summary

The goal of this project is to develop novel targets with significant therapeutic potential to enhance cellular clearance functions in the RPE in order to protect these cells against cell death. The goal of this project is to develop effective therapeutic strategies to induce cellular clearance in the RPE. Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal function. We hypothesize that induction of TFEB will alleviate substrate accumulation in the RPE. We propose in Specific Aim1, to study the functional effects of gene transfer of constitutively active TFEB in enhancing lysosomal function and autophagy in the RPE. In Specific Aim 2, we will study the cellular effects of inhibiting micro-RNA (miRNA)-mediated suppression of TFEB expression.

Project Details

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.