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
Marchette, L D; Sherry, D M; Brush, R S et al. (2014) Very long chain polyunsaturated fatty acids and rod cell structure and function. Adv Exp Med Biol 801:637-45
Rajala, Raju V S; Rajala, Ammaji; Morris, Andrew J et al. (2014) Phosphoinositides: minor lipids make a major impact on photoreceptor cell functions. Sci Rep 4:5463
Bennett, Lea D; Hopiavuori, Blake R; Brush, Richard S et al. (2014) Examination of VLC-PUFA-deficient photoreceptor terminals. Invest Ophthalmol Vis Sci 55:4063-72
Agbaga, Martin-Paul; Logan, Sreemathi; Brush, Richard S et al. (2014) Biosynthesis of very long-chain polyunsaturated fatty acids in hepatocytes expressing ELOVL4. Adv Exp Med Biol 801:631-6
Bennett, Lea D; Brush, Richard S; Chan, Michael et al. (2014) Effect of reduced retinal VLC-PUFA on rod and cone photoreceptors. Invest Ophthalmol Vis Sci 55:3150-7
Logan, Sreemathi; Agbaga, Martin-Paul; Chan, Michael D et al. (2014) Endoplasmic reticulum microenvironment and conserved histidines govern ELOVL4 fatty acid elongase activity. J Lipid Res 55:698-708
Logan, Sreemathi; Anderson, Robert E (2014) Dominant Stargardt Macular Dystrophy (STGD3) and ELOVL4. Adv Exp Med Biol 801:447-53
Woodruff, Michael L; Rajala, Ammaji; Fain, Gordon L et al. (2014) Modulation of mouse rod photoreceptor responses by Grb14 protein. J Biol Chem 289:358-64
Agbaga, Martin-Paul; Tam, Beatrice M; Wong, Jenny S et al. (2014) Mutant ELOVL4 that causes autosomal dominant stargardt-3 macular dystrophy is misrouted to rod outer segment disks. Invest Ophthalmol Vis Sci 55:3669-80
Rajala, Ammaji; Wang, Yuhong; Zhu, Ye et al. (2014) Nanoparticle-assisted targeted delivery of eye-specific genes to eyes significantly improves the vision of blind mice in vivo. Nano Lett 14:5257-63

Showing the most recent 10 out of 165 publications