Defining the Functional Role of RPE-Expressed AMD Risk-Associated Long Non-Coding RNAs

Summary

We aim to elucidate the role two novel long non-coding RNAs play in the regulation of HTRA1, a gene associated with high risk of developing AMD. The long non-coding RNAs are predicted, and our data demonstrates, to decrease HTRA1 levels. The data obtained in this proposal will be used to advance our knowledge of AMD pathogenesis, and ultimately, toward a therapeutic intervention.

Project Details

The goal of our project is to study the expression and function of two novel long non-coding RNAs (lncRNAs) that are located in the HTRA1/ARMS2 risk loci. We hypothesize that these novel lncRNAs control the expression of ARMS2 and HTRA1, and this expression is affected in individuals with AMD.  We will test this hypothesis by studying the expression of the novel lncRNAs in the retina from AMD-affected donor eyes and compare this expression to normal donor eyes. Bioinformatic analysis of the novel lncRNAs suggests they are processed into short interfering RNAs, which are known to repress gene expression. We will test their function by over-expressing them in induced pluripotent stem cell-derived retinal pigment epithelial cells and quantify the change in expression of HTRA1 and ARMS2.

This study is unique in that it is the first to identify the expression of lncRNAs in any of the AMD risk loci. Since none of the protein-coding genes have been proven to be causative for AMD pathogenesis, this study will begin to shed light on the role played by non-coding RNAs.