Abstract

A general understanding of the metabolic needs of photoreceptors could lead to broadly applicable therapeutic strategies to treat retinas stressed by diverse genetic and environmental factors. With that in mind, we have been investigating the fundamental nature of energy metabolism in the retina and the retinal pigment epithelium (RPE). Photoreceptor metabolism is limited by the availability of nutrients from the RPE. Evidence indicates that the retina and RPE function together as a network of metabolically specialized and interdependent cells. We hypothesize that a deficiency in any component of that network could lead to retinal degeneration as part of the failure of the entire metabolic ecosystem. Our recent findings support this hypothesis. We have proposed a model in which the flow of glucose from the choroidal blood through the RPE to the retina is enhanced by lactate produced by glycolysis in photoreceptors. Lactate not only fuels the RPE, but it also can influence the differentiation state of RPE cells. These observations are the basis for the specific aims of this proposal.
The first aim will explore ways to enhance the flow of glucose across the RPE.
The second aim will investigate how lactate influences differentiation of RPE cells. This project will identify ways to enhance the flow of glucose across the RPE to the retina. Our findings can be used to design therapeutic approaches that make photoreceptors in an eye more robust and resistant to genetic and environmental factors that normally would cause photoreceptor degeneration. .

Public Health Relevance

The retina and the retinal pigment epithelium each have unique and specialized metabolic functions. Our recent findings show that the specialized metabolic features of these tissues contribute to an essential symbiotic metabolic relationship between the retina and RPE. Findings from the experiments in this proposal will expedite the understanding of underlying causes of many forms of blindness and the decline of vision that occurs with aging.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY017863-09
Application #
9522429
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Neuhold, Lisa
Project Start
2007-09-15
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

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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