Fluorescent Cell Death Probes for the Early Detection and Inhibition of Age-Related Macular Degeneration

Significant advances in the molecular understanding of CNV pathogensis have led to an FDA-approved vision-improving therapy [1.2]. In contrast, GA pathogenesis is still nebulous and there are no FDA-approved therapties for the 1 million people in the US who already have GA and the millions more who are at risk. This proposal focuses on the critical biological question of how programmed cell death occurs in the aging human retina during atrophis AMD. We have recently discovered a specific double-stranded RNA (ds RNA) sequence, identified as Alu RNA, a widely known genetic mobile element, in human eyes affected wth GA. Exposure to Alu results in widespread RPE cell death in vivo in an animal model and in citro with human primary cell isolates [3]. Based on work from my previous studies of dsRMA mediated reinotoxicity, we have identified several caspase dependent events that occur duirng this programmed cell deaht of the RPE. However, the primary ceptor that interacts with this dsRMA moleculre as well as convergence and redundancy of cell death signaling in atrophic AMD remains unclear. The work conducted with this award will resolve the specific pro-apototic proease detection and ihnibition as a modaltiy for visualizing disease activity and preventing progression. This data could significantly hasten the day when there is a safe and effective treatment to prevent the loss of vision and precious quality of life due to atrophic AMD.