Intracellular crosstalk mediated by phosphoinositides is fundamentally important for understanding regulation of cellular function. The specific objective of this application is to investigate the role of phosphoinositide 3-kinase (PI3K) in the metabolic regulation of the retina, specifically the glycolytic pathways that activate the pentose phosphate pathway to generate NADPH, which is required for anabolic and antioxidant pathways that are essential for cone survival. We hypothesize that PI3K signaling provides neuroprotection and regulates cellular processes required for promoting and sustaining photoreceptor functionality and viability. The study proposed here will define how PI3K regulates photoreceptor functions. Using genetically modified mice and pharmacological agents, we have documented changes in cellular redox and metabolic gene expression. We also developed methods for manipulating PI3K and pyruvate kinase (PKM2) in the retina and for detecting anabolic functions and cellular redox changes. We will use these methods to determine how PI3K regulates PKM2 activity and other cellular functions. We will study the mechanisms of cone cell death in cone PI3K knockout and other mouse models of cone degeneration (Aim 1). We will test ways to rescue sick and dying cones that are genetically pre-determined to degenerate (Aim 2).

Public Health Relevance

The retina lives in a hostile environment and is exposed daily to genetic and metabolic stresses. To survive, the retina has developed remarkable protective mechanisms. Our long-term goal is to understand these mechanisms as a foundation on which novel drug therapies can be designed to protect retinal function in patients who suffer from retinal degenerations.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY000871-42
Application #
9252461
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Neuhold, Lisa
Project Start
1995-02-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
42
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Rajala, Raju V S; Rajala, Ammaji (2018) Redundant and Nonredundant Functions of Akt Isoforms in the Retina. Adv Exp Med Biol 1074:585-591
Rajala, Ammaji; Wang, Yuhong; Brush, Richard S et al. (2018) Pyruvate kinase M2 regulates photoreceptor structure, function, and viability. Cell Death Dis 9:240
Rajala, Ammaji; Wang, Yuhong; Rajala, Raju V S (2018) Constitutive Activation Mutant mTOR Promote Cone Survival in Retinitis Pigmentosa Mice. Adv Exp Med Biol 1074:491-497
Wang, Yuhong; Rajala, Ammaji; Rajala, Raju V S (2018) Nanoparticles as Delivery Vehicles for the Treatment of Retinal Degenerative Diseases. Adv Exp Med Biol 1074:117-123
Agbaga, Martin-Paul; Merriman, Dana K; Brush, Richard S et al. (2018) Differential composition of DHA and very-long-chain PUFAs in rod and cone photoreceptors. J Lipid Res 59:1586-1596
Hopiavuori, Blake R; Deák, Ferenc; Wilkerson, Joseph L et al. (2018) Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency. Mol Neurobiol 55:1795-1813
Hopiavuori, Blake R; Agbaga, Martin-Paul; Brush, Richard S et al. (2017) Regional changes in CNS and retinal glycerophospholipid profiles with age: a molecular blueprint. J Lipid Res 58:668-680
Simón, María Victoria; Agnolazza, Daniela L; German, Olga Lorena et al. (2016) Synthesis of docosahexaenoic acid from eicosapentaenoic acid in retina neurons protects photoreceptors from oxidative stress. J Neurochem 136:931-46
Wang, Yuhong; Rajala, Ammaji; Cao, Binrui et al. (2016) Cell-Specific Promoters Enable Lipid-Based Nanoparticles to Deliver Genes to Specific Cells of the Retina In Vivo. Theranostics 6:1514-27
Bennett, Lea D; Anderson, Robert E (2016) Current Progress in Deciphering Importance of VLC-PUFA in the Retina. Adv Exp Med Biol 854:145-51

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