Studies from our laboratory over the past two decades have shown that the retina and rod outer segments (ROS) have an active phosphoinositide (PI) metabolism (called PI Cycle) that generates several lipid second messengers. We have reported previously that light stimulates various components of the PI Cycle in vertebrate ROS, including DG kinase, PI synthetase, PIP kinase (PIPK), phospholipase C (PLC), and PI 3-kinase (PI3K). We have reported that G-protein coupled receptor rhodopsin regulates the phosphorylation of retinal insulin receptor in vivo and activates PI3K, which forms PI-3,4,5-P3 and other D3-phosphorylated PIs in ROS. In other tissues, these second messengers have been shown to affect a large number of intracellular events, including secretion, cell survival, membrane trafficking, and actin polymerization, all of which are important in the retina. It is our hypothesis that light-stimulation of this reaction in photoreceptor cell outer segments affects important photoreceptor cell function(s) not related to visual transduction. The long-term goal of our research is to elucidate the physiological role of these lipid second messengers in photoreceptor cells. Recently we have reported that deletion downstream effectors of PI3K, Akt2 and Bcl-xl, resulted in stress-induced photoreceptor degeneration. These studies clearly suggest that PI3K generated phosphoinositides are important regulators of photoreceptor survival and maintenance. To this end we will determine the functional role of PI3K in photoreceptor cells, identify and characterize protein targets for 3-phosphorylated phosphoinositides, determine Akt2 interacting proteins that are necessary for cell survival, and determine the mechanism of regulation of PI-4,5-P2 levels in rod outer segments. We will utilize a combination of genetic, molecular biological, and biochemical approaches to address the proposed studies. Results of these studies will lead to a better understanding of the role of PI3K generated phosphoinositides in photoreceptor structure, function, and survival.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY000871-37
Application #
7742157
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
1995-02-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
37
Fiscal Year
2010
Total Cost
$362,588
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
73117
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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