The overall goal of our research program is to gain a greater understanding of the intercellular and intracellular signaling pathways that provide neuroprotection of both rod and cone photoreceptor cells. The specific objective of this renewal application is to investigate the role of phosphoinositides (PI), particularly those produced by phosphoinositide 3-kinase (PI3K), in this process. Studies from our laboratory over the past two decades have shown that the retina and both rod and cone outer segments have an active PI metabolism. Interestingly, conditional deletion of class I PI3K from cones resulted in an age-related cone degeneration and the phenotype was not rescued by healthy rods, suggesting that rod-derived cone survival factors may signal through cone PI3K.
The Aims of the proposed research are: 1) to define the relationship between the phosphoinositide signaling pathway and cone survival, 2) to search for the mechanisms of cone cell death in retinas with rod-specific mutations, and 3) find ways to rescue sick and dying cones. It is our hypothesis that PI3K-generated PIs provide neuroprotection and regulate cellular processes requisite for promoting and sustaining cone photoreceptor functionality and viability. In humans, age-related macular degeneration and diabetic retinopathy are the most common disorders affecting cones. Cones also are affected indirectly in diseases such as retinitis pigmentosa and directly in cone and cone-rod dystrophies. Achieving the above Aims will provide the basis for the development of novel therapeutic interventions to prevent the progressive and irreversible loss of cone viability, structural integrity, and function.

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 #
2R01EY000871-40A1
Application #
8696202
Study Section
Special Emphasis Panel (BVS)
Program Officer
Neuhold, Lisa
Project Start
1995-02-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
40
Fiscal Year
2014
Total Cost
$370,000
Indirect Cost
$120,000
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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