Department of Ophthalmology
West Virginia University School of Medicine
Morgantown, WV

BASIC RESEARCH PROJECT
Nutritional strategies in Age-related Macular Degeneration

Research Interests

Scientific Summary: Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. There are currently no effective treatments available for “dry” or atrophic AMD, which includes the earlier loss of retinal pigment epithelial (RPE) cells. Dr. Du recently used an unbiased approach to study the nutritional consumption in human RPE cells and found that RPE prefers to use an amino acid, proline, to support its energy metabolism. Interestingly, RPE converts the proline into key intermediates in metabolism and exports these intermediates to fuel the retina. The preliminary data confirm that the RPE supports retinal energy metabolism through proline in vivo and supplementation of proline in RPE or diet could protect oxidative damage and improve age-related visual decline. Consistently, the mutations of genes associated with proline metabolism in patients have been known to cause retinal degeneration. Findings and published results suggest that proline metabolism is fundamentally important to the pathogenesis of AMD.

The objective is to study how this special amino acid is associated with retinal function and degeneration, and to test the treatment with proline on an AMD-like disease model. Study findings will allow Dr. Du to better understand how energy metabolism impacts retinal degeneration and provide the foundation for developing novel nutrition-based therapies for AMD.

Plans for 2021
Purpose of Project: The purpose of this project is to study the role of proline metabolism in retinal function and viability, and to develop nutritional approach to treat AMD.

Dr. Du will continue to investigate proline metabolism in retinal function and disease.  He plans to determine the role of proline utilization in the metabolic communication between the retina and RPE, and in retinal degeneration buy using the inducible RPE-specifically knockout of the proline transporter SLC6A20 in vivo.    Dr. Du’s research team will also aim to understand the mechanisms of how proline protects against oxidative damage and improves retinal degeneration.

Specific Aims:
Aim 1: Determine the role of proline transport in retinal metabolism and health in vivo.  The research team will test the hypothesis that the proline transporter SLC6A20 is responsible for proline utilization to fuel retinal metabolism and maintain retinal health. Dr Du’s team will measure metabolic, functional, and morphological changes in the inducible RPE-specific knockout of SLC6A20 in mice.

Aim 2: Determine the role of dietary proline in retinal metabolism and its protection of age-related visual decline.  Dr. Du’s research will test the hypothesis that dietary proline will boost retinal mitochondrial metabolism to protect against age-related retinal degeneration.  They will determine the role of proline-enriched and proline-deficient diets on retinal mitochondrial metabolism, visual function, and retinal morphology in mice.

Progress in 2020
Dr. Du made significant progress in 2020.  His research team generated inducible RPE-specific SLC6A20A knockout mice and whole body SLC6A20A mice and found that SLC6A20 and other proline metabolism genes are highly upregulated in the RPE.  The inhibition of mitochondrial respiration in RPE blocked proline utilization to disrupt the nutrient transport to the retina.   Additionally, Dr. Du’s research found a proline-enriched diet increases the biosynthesis of glutothione and NADPH, protects oxidative damage, and improves visual function in an acute AMD-like mouse model. Dr. Du’s research resulted in six publications in 2020.

2020 Publications

Progress in 2019

In 2019, Dr. Du found proline protects retinal pigment epithelium (RPE) against oxidative damage both in vitro and in vivo. Dietary proline supplement improves visual function in an AMD-like mouse model.  These new findings were presented at ARVO 2019 in Vancouver and were also published.  Additionally, Dr. Du generated floxed mice targeting proline transporter SLC6A20 and validated a new inducible RPE CRE mouse line.

Specific Aims: Aim 1: Investigate how proline utilization impacts retinal function and viability. We will generate a mouse line to block proline utilization in RPE by deletion of the proline transporter SLC6A20. We will test how the limited proline utilization in RPE affects retinal metabolism, visual function and retinal degeneration. Aim 2: Rescue an AMD-like retinal degeneration model by proline supplementation. We will test whether proline supplementation will rescue RPE damage and protect photoreceptor cell death in an AMD-like retinal degeneration model.

Results Previously Published: Dr. Du’s research team and other groups have published results showing that proline metabolism is linked to retinal degeneration, SLC6A20 expresses almost exclusively in RPE with its expression correlated with proline consumption, and proline is an important nutrient in energy metabolism, anti-aging and stress protection.