Osmotic regulation in the cone dystrophy, CDSRR

About This Grant

Project Summary Vision is our primary sense. We rely on vision for everything from building our sense of reality, to navigating obstacles, identifying threats, and reading text and emotions. Untreatable vision loss beginning in childhood is often emotionally devastating and incurs a lifetime of healthcare expenses. This is the situation for people with Cone Dystrophy with Supernormal Rod Response (CDSRR), alternatively referred to as KCNV2 Retinopathy. In CDSRR there is a decline of vision in early childhood, followed by progressive macular degeneration by early adulthood. The hindrance to developing sight preserving treatments for CDSRR is that the etiology of macular degeneration is unknown. CDSRR is caused by mutations in a photoreceptor-specific potassium channel, Kv2.1/Kv8.2. As such CDSRR can be considered a disease of disrupted potassium homeostasis in the outer retina. Regulated potassium flux is essential for the electrical response of photoreceptors to light and can create osmotic gradients that drive water transport. Since photoreceptors have a high rate of mitochondrial respiration, generating excess metabolic wastewater that must be exported, we propose that loss of Kv2.1/Kv8.2 potassium channels in CDSRR reduces clearance of wastewater from photoreceptors, activating chronic osmotic stress signaling. In this project, we will use state-of- the-art imaging biomarkers and transcriptomics to evaluate osmotic regulation in mouse models of CDSRR.