Targeted Proline Metabolism in Age-Related Macular Degeneration

We previously report that proline, an amino acid, is a critical nutrient source for retinal pigment epithelium (RPE) and retina. We found supplementation with proline could protect photoreceptor degeneration in a mouse model of age-related macular degeneration (AMD), and RPE from AMD patient donors have poor utilization of proline. In this proposal, we will test mechanisms for proline utilization in AMD and investigate approaches to rescue RPE defect from AMD by targeting proline metabolism.

The goal of this project proposal is to study the role of proline metabolism in retinal pigment epithelium (RPE) cells from age-related macular degeneration (AMD) donors as the first step to developing a nutritional treatment for AMD. The RPE maintains the health of the neural retina by performing critical functions, including nutrient transport, phagocytosis of the outer segment, and secretion of cytokines. These RPE-specific processes rely on the active energy metabolism of nutrients, such as proline, to maintain their unique functions. The dysfunctional RPE metabolism is a key factor that contributes to the pathology of AMD. We recently found that RPE prefers to use proline to fuel its metabolism but RPE cells from AMD donors could not efficiently use proline to fuel their metabolism.

In Aim 1, we will fully evaluate proline metabolism in RPE donor cells. By using different approaches to investigate the genes, substrates, and products that are related to proline metabolism, we will know why AMD cells could not efficiently utilize proline. In Aim 2, we study the impact of reduced proline utilization on mitochondrial function. Mitochondria is the powerhouse for energy metabolism. By measuring mitochondrial function, we will understand how proline metabolism influences mitochondrial energy production. In Aim 3, we will test to rescue energy deficiency in AMD donor cells by improving the utilization of proline. We will test different approaches to increase the availability of proline in AMD cells and evaluate its rescue on mitochondrial dysfunction in the donor cells. Our findings will finally determine how RPE mitochondrial proline metabolism is impaired in AMD and whether proline supplementation has a positive effect on mitochondrial function. The strategy to target proline metabolism will provide the foundation for developing new treatments for AMD.