NAD Metabolism in Normal and Disease-Specific Human Retinal Pigment Epithelial Cells

Summary

Some eye diseases, like age-related macular degeneration (AMD), cause blindness because the light-sensing cells and their support cells in the eye, which are known as retinal pigment epithelium cells, stop working. We believe that one of the reasons the support cells stop working is because their ability to generate energy for themselves is damaged. We would like to understand how this damage occurs and to test whether new nutritional supplements, called nicotinamide adenine dinucleotide (NAD) metabolites, can improve their ability to continue to survive and function. If these new supplements can rescue the support cells when studied in a cell culture dish and in a mouse model, we believe they may be able to slow or stop vision loss in patients with AMD and other similar retinal diseases.

Project Details

The goal of this project is to understand how energy metabolism is altered in AMD and test a nutritional approach to boost metabolism to prevent or rescue dry AMD. Retinal pigment epithelium (RPE) cells are extremely active in metabolism in nourishing the light-sensing photoreceptors. When energy metabolism in RPE cells drops, that can lead to the death of photoreceptors and cause blindness in AMD.

NAD is a key molecule controlling energy metabolism and its level is dramatically decreased in human RPE cells under oxidative damage. NAD levels also drop in RPE cells derived by stem cell technology from patients with Sorsby Fundus Dystrophy (SFD), an inherited retinal degenerative disease with very similar clinical features to AMD. We plan to study how NAD is reduced in diseased RPEs and to supplement NAD precursor proteins in an attempt to rescue blindness in an AMD animal model.

We have three aims to achieve our goal. First, we will use state-of-the-art carbon tracing technology to study how mechanisms associated with oxidative stress, a common risk factor in AMD, cause the decrease of NAD. Next, we will generate patient-derived RPE cells from SFD patients and understand the NAD metabolism in these cells. Finally, we will supplement different NAD precursors to boost metabolism to rescue the RPE derived from SFD patient as well as retinal degeneration in mice in vivo. The completion of this project will provide insight into the metabolic basis for AMD and will potentially yield a new nutritional approach to prevent or slow down blindness.

Our project is innovative because it seeks to characterize a new mechanism of oxidative damage in RPE while developing novel NAD-based therapeutics to slow or prevent retinal degeneration. This will be accomplished by using advanced technologies in mass spectrometry and disease-specific stem cell-derived RPE.