A New Method to Decrease Cell Death by Supplementation with NAD Metabolites

Jianhai Du, PhD
West Virginia University (Morgantown, WV)

Co-Principal Investigators

Jennifer Chao, MD, PhD
University of Washington
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2019
Disease:
Macular Degeneration
Award Amount:
$160,000
Grant Reference ID:
M2016047
Award Type:
Standard
Award Region:
US Southeastern

This grant is made possible in part by support from the Ivan Bowen Family Foundation.

Jianhai Du, PhD

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 epithelilum 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.

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.

About the Researcher

Jianhai Du, PhD is an assistant professor of ophthalmology and of biochemistry at West Virginia University. His research interest is to understand the energy metabolism in the retina and identify the metabolic basis for retinal degenerative diseases, including age-related macular degeneration (AMD) and inherited forms of retinal degeneration. The goal is to use this knowledge to prevent or slow down retinal degeneration in patients.

Dr. Du received his PhD from Peking University in China in 2006, studying cell signaling in cardiac proliferation. He did his postdoctoral research at Medical College of Wisconsin, where he studied post-translational regulation of pterin metabolism in ischemic heart diseases, and later in the lab of James B. Hurley, PhD, at the University of Washington, where he developed stable isotope methodologies to measure metabolic flux in retinal and human RPE cells. Dr. Du was appointed to serve as acting instructor of biochemistry in 2012, and was promoted to research assistant professor of ophthalmology at University of Washington in 2015. In July 2016, he joined the faculty of West Virginia University. Dr. Du’s research has been supported by funding from the American Heart Association, The Knights Templar Eye Foundation, and the National Eye Institute.

Personal Story

I am very grateful to Brightfocus Foundation and millions of generous donors to support my research. As a junior faculty member, I will start my lab with this precious seed funding. It, as well as other support, will help to build up an active research team to study metabolism in retinal diseases.

The human retina has a unique metabolism and understanding the mystery of its metabolism would potentially pave the way for new treatments in retinal degenerative diseases. Photoreceptors consume enormous amount of energy every second for visual functions; however their energy production is different from other neurons and normal tissues, and similar to that of cancer cells. Retinal pigment epithelium is tightly coupled with photoreceptors in metabolic regulation and retinal cell survival. With this award, I will strive to understand a critical metabolic pathway using patient specific stem cell-derived cells, and to develop a metabolism-based treatment in AMD models which hopefully will be translated so that it is applicable to human patients in the future.

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