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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY017863-05
Application #
8433945
Study Section
Special Emphasis Panel (BVS)
Program Officer
Neuhold, Lisa
Project Start
2006-12-01
Project End
2016-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$383,976
Indirect Cost
$133,976
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Lindsay, Ken J; Du, Jianhai; Sloat, Stephanie R et al. (2014) Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina. Proc Natl Acad Sci U S A 111:15579-84
Adijanto, Jeffrey; Du, Jianhai; Moffat, Cynthia et al. (2014) The retinal pigment epithelium utilizes fatty acids for ketogenesis. J Biol Chem 289:20570-82
Du, Jianhai; Cleghorn, Whitney; Contreras, Laura et al. (2013) Cytosolic reducing power preserves glutamate in retina. Proc Natl Acad Sci U S A 110:18501-6
Du, Jianhai; Cleghorn, Whitney M; Contreras, Laura et al. (2013) Inhibition of mitochondrial pyruvate transport by zaprinast causes massive accumulation of aspartate at the expense of glutamate in the retina. J Biol Chem 288:36129-40
Chertov, Andrei O; Holzhausen, Lars; Kuok, Iok Teng et al. (2011) Roles of glucose in photoreceptor survival. J Biol Chem 286:34700-11
Linton, Jonathan D; Holzhausen, Lars C; Babai, Norbert et al. (2010) Flow of energy in the outer retina in darkness and in light. Proc Natl Acad Sci U S A 107:8599-604