Metabolic demands of photoreceptors in darkness are qualitatively different than in light. In darkness their metabolism is like that of conventiona neurons. It is devoted mostly to supplying energy to ion pumps. In light their metabolism is more like that of cancer cells. Illumination lowers energy requirements for ion pumping but it increases the demand for anabolic activity to synthesize new membranes and regenerate rhodopsin. Cyclic GMP and Ca2+ play central roles in the way photoreceptors respond and adapt to light. Genetic deficiencies that alter the synthesis or degradation of cGMP cause degeneration of photoreceptor cells. We hypothesize that GMP and Ca2+ influence basic metabolic activities in photoreceptors that support their function and viability. We are investigating relationships between metabolic needs of photoreceptors and photoreceptor survival. We developed biochemical assays that evaluate photoreceptor metabolism and we found that chronic accumulation of cGMP causes massive depletion of glutamic acid, a condition that precludes synthesis of proteins and glutathione.
One aim of this proposal is to test the hypothesis that depletion of glutamate is the reason photoreceptors degenerate in certain types of inherited retinal degenerative diseases. We will explore the possibility that nutritional supplements can block photoreceptor degeneration in animal models of these disease states. Metabolism and viability also depend on environment. Photoreceptors can survive for days in culture in an intact retina, but they degenerate within hours when dissociated from the retina.
The second aim of this proposal is to investigate the metabolic basis for degeneration of dissociated photoreceptors by characterizing metabolic effects of small molecules that enhance photoreceptor survival. We will use this information to help identify fundamental metabolic requirements of photoreceptors.

Public Health Relevance

Retinal degenerative diseases aren't yet treatable, partly because relationships between genetic disruptions, metabolic consequences of the disruptions and cell death are unknown. Gene therapy may develop into a very effective approach for treatment, but there still are hurdles to overcome before that approach will be safe and effective. Our study will yield a fundamental understanding of why specific mutations cause photoreceptor death. Our findings also may lead to simple nutritional therapies that could be used to enhance treatment of blindness caused by retinal degeneration.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BVS)
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Neuhold, Lisa
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University of Washington
Schools of Medicine
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Du, Jianhai; An, Jie; Linton, Jonathan D et al. (2018) How Excessive cGMP Impacts Metabolic Proteins in Retinas at the Onset of Degeneration. Adv Exp Med Biol 1074:289-295
Rajala, Ammaji; Wang, Yuhong; Brush, Richard S et al. (2018) Pyruvate kinase M2 regulates photoreceptor structure, function, and viability. Cell Death Dis 9:240
Zhu, Siyan; Yam, Michelle; Wang, Yekai et al. (2018) Impact of euthanasia, dissection and postmortem delay on metabolic profile in mouse retina and RPE/choroid. Exp Eye Res 174:113-120
Chao, Jennifer R; Knight, Kaitlen; Engel, Abbi L et al. (2017) Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side. J Biol Chem 292:12895-12905
Kanow, Mark A; Giarmarco, Michelle M; Jankowski, Connor Sr et al. (2017) Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye. Elife 6:
Hurley, James B (2017) Warburg's vision. Elife 6:
Du, Jianhai; Rountree, Austin; Cleghorn, Whitney M et al. (2016) Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina. J Biol Chem 291:4698-710
Du, Jianhai; Yanagida, Aya; Knight, Kaitlen et al. (2016) Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium. Proc Natl Acad Sci U S A 113:14710-14715
Zhang, Lijuan; Du, Jianhai; Justus, Sally et al. (2016) Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration. J Clin Invest 126:4659-4673
Contreras, Laura; Ramirez, Laura; Du, Jianhai et al. (2016) Deficient glucose and glutamine metabolism in Aralar/AGC1/Slc25a12 knockout mice contributes to altered visual function. Mol Vis 22:1198-1212

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