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 #
5R01EY000871-38
Application #
7995198
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
1995-02-01
Project End
2012-08-31
Budget Start
2010-12-01
Budget End
2012-08-31
Support Year
38
Fiscal Year
2011
Total Cost
$351,600
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
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
Rajala, Raju V S; Rajala, Ammaji; Kooker, Christopher et al. (2016) The Warburg Effect Mediator Pyruvate Kinase M2 Expression and Regulation in the Retina. Sci Rep 6:37727
Azadi, Seifollah; Brush, Richard S; Anderson, Robert E et al. (2016) Class I Phosphoinositide 3-Kinase Exerts a Differential Role on Cell Survival and Cell Trafficking in Retina. Adv Exp Med Biol 854:363-9
Rajala, Raju V S; Kanan, Yogita; Anderson, Robert E (2016) Photoreceptor Neuroprotection: Regulation of Akt Activation Through Serine/Threonine Phosphatases, PHLPP and PHLPPL. Adv Exp Med Biol 854:419-24
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
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
Zulliger, Rahel; Naash, Muna I; Rajala, Raju V S et al. (2015) Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase-activating protein-1 leads to leber congenital amaurosis-1. J Biol Chem 290:3488-99
Woodruff, Michael L; Rajala, Ammaji; Fain, Gordon L et al. (2015) Effect of knocking down the insulin receptor on mouse rod responses. Sci Rep 5:7858
Gupta, Vivek K; Rajala, Ammaji; Rajala, Raju V S (2015) Non-canonical regulation of phosphatidylinositol 3-kinase gamma isoform activity in retinal rod photoreceptor cells. Cell Commun Signal 13:7
Rajala, Raju V S; Ranjo-Bishop, Michelle; Wang, Yuhong et al. (2015) The p110α isoform of phosphoinositide 3-kinase is essential for cone photoreceptor survival. Biochimie 112:35-40

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