This proposal addresses 2 of the program objectives of the NEI Retinal Diseases Panel: - "Explore the topographical and regional differences of the retina and the relationship of this topography to disease progression". - "Continue to develop and apply noninvasive technologies such as functional magnetic resonance imaging (fMRI), ocular coherence tomography, adaptive optics, and confocal imaging to better understand retinal function and changes in disease states". The overall purpose of this proposal is to characterize the topography of the cone mosaic in normal and diseased retinae, to examine the factors that might govern this topography, and to assess photoreceptor function in these mosaics. I have discovered novel cone degeneration mechanisms linked to mutations in the cone photopigments. The experiments in this proposal will help clarify the deleterious effects of disruptions in cone pigment expression, both on the appearance of the cone mosaic and on visual performance. This proposal is the first step in an effort to build a research program that will contribute to the understanding of fundamental biological processes underlying cone vision and vision disorders. By examining how topographical disruptions in the cone mosaic affect visual function (contrast sensitivity, acuity, sensitivity), I will gain novel insight into the structure-function relationship on a cellular level. Moreover, the methodological approach developed in this proposal will be translatable to other retinal diseases that are more complex in nature. Through a unique collaborative effort, I propose to combine psychophysical, electrophysiological, and genetic techniques with in vivo imaging techniques (such as optical coherence tomography &adaptive-optics ophthalmoscopy) to address the following aims:
Specific Aim 1 - Characterize the S-cone submosaic in normal and tritan subjects and its relationship to the overall topography of the retina.
Specific Aim 2 - Examine the effects of mutations in the L/M-photopigment gene array on the viability of the cones and the organization of the photoreceptor mosaic.
Specific Aim 3 - Determine the consequences of cone-opsin mutations and disorganization of the cone mosaic for cone and visual system function.

Public Health Relevance

The majority of our visual activity relies on the cone photoreceptors in the retina. This proposal employs a multidisciplinary approach (using high-resolution retinal imaging, genetic analysis, and electrophysiological tests) to investigate how mutations in the cone pigments affect cone-photoreceptor structure &function. The work in this proposal will serve as the foundation for translation of this same approach to the future study of other retinal degenerations, which will accelerate progress for the effective implementation of novel therapies.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
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Medical College of Wisconsin
Schools of Medicine
United States
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Aboshiha, Jonathan; Dubis, Adam M; Cowing, Jill et al. (2014) A prospective longitudinal study of retinal structure and function in achromatopsia. Invest Ophthalmol Vis Sci 55:5733-43
Sundaram, Venki; Wilde, Caroline; Aboshiha, Jonathan et al. (2014) Retinal structure and function in achromatopsia: implications for gene therapy. Ophthalmology 121:234-45
Liu, Benjamin S; Tarima, Sergey; Visotcky, Alexis et al. (2014) The reliability of parafoveal cone density measurements. Br J Ophthalmol 98:1126-31
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Dubow, Michael; Pinhas, Alexander; Shah, Nishit et al. (2014) Classification of human retinal microaneurysms using adaptive optics scanning light ophthalmoscope fluorescein angiography. Invest Ophthalmol Vis Sci 55:1299-309
Wilk, Melissa A; McAllister, John T; Cooper, Robert F et al. (2014) Relationship between foveal cone specialization and pit morphology in albinism. Invest Ophthalmol Vis Sci 55:4186-98
Flatter, John A; Cooper, Robert F; Dubow, Michael J et al. (2014) Outer retinal structure after closed-globe blunt ocular trauma. Retina 34:2133-46
Dubis, Adam M; Cooper, Robert F; Aboshiha, Jonathan et al. (2014) Genotype-dependent variability in residual cone structure in achromatopsia: toward developing metrics for assessing cone health. Invest Ophthalmol Vis Sci 55:7303-11
Langlo, Christopher S; Flatter, John A; Dubra, Alfredo et al. (2014) A lensing effect of inner retinal cysts on images of the photoreceptor mosaic. Retina 34:421-2
Scoles, Drew; Higgins, Brian P; Cooper, Robert F et al. (2014) Microscopic inner retinal hyper-reflective phenotypes in retinal and neurologic disease. Invest Ophthalmol Vis Sci 55:4015-29

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