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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Oklahoma Health Sciences Center
Schools of Medicine
Oklahoma City
United States
Zip Code
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
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
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
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
Rajala, Ammaji; Wang, Yuhong; Rajala, Raju V S (2016) Activation of oncogenic tyrosine kinase signaling promotes insulin receptor-mediated cone photoreceptor survival. Oncotarget 7:46924-46942
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
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 p110? isoform of phosphoinositide 3-kinase is essential for cone photoreceptor survival. Biochimie 112:35-40

Showing the most recent 10 out of 181 publications