and Relevance The inherent autofluorescence (AF) of the fundus originates from RPE bisretinoid lipofuscin. While RPE lipofuscin is amassed even in healthy eyes, imaging of fundus AF by confocal scanning laser ophthalmoscopy (cSLO) has shown that the patterns and intensities of AF deviate from normal in several retinal disorders. Accordingly, we previously demonstrated that a standardized approach to quantifying short wavelength fundus AF (qAF) can assist in the diagnosis of retinal disease, in the monitoring of disease progression and in the assessment of therapeutic outcomes. To enable these investigations we have gathered normative qAF data from a large number of participants with healthy eye status (aged 6-60) so as to establish ranges of qAF values with respect to age, gender and ethnicity. Going forward we will use these normal values to determine whether bisretinoid lipofuscin accumulation, a cellular burden that distinguishes RPE cells, confers susceptibility to the adverse effects of HCQ on retina and whether qAF levels in inferior macula can serve as an early sign of HCQ toxicity (Specific Aim 1). We will also determine why female carriers of choroideremia, present with reduced RPE lipofuscin measured as qAF (Specific Aim 2). Using the qAF approach we will test for a relationship between the loss of the ellipsoid zone in SD-OCT images and changes in short wavelength fundus autofluorescence (SW-AF) intensities in patients diagnosed with central serous chorioretinopathy (Specific Aim 3). Homozygous mutations in ABCA4 are well known to confer elevated qAF although the spatial distribution of the fluorescence intensity is not uniform. By multi-modal imaging we will elucidate the underlying structural basis of this topographic distribution (Specific Aim 4). In summary, the studies proposed in this application will examine the contribution that the lipofuscin of retina makes to the onset and progression of several retinal diseases and will demonstrate that quantitation of fundus AF facilitates the diagnosis and monitoring of some retinal disorders.

Public Health Relevance

Retinal degeneration remains a major cause of legal blindness. Despite advances in the genetics of retinal degeneration, associated pathogenic processes largely defy elucidation. The work proposed will address disease mechanisms that may be influential in not only monogenic retinal diseases (choroideremia, recessive Stargardt disease) but also central serous chorioretinopathy (CSC) and hydroxychloroquine-induced retinal toxicity.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Shen, Grace L
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Tanaka, Koji; Lee, Winston; Zernant, Jana et al. (2018) The Rapid-Onset Chorioretinopathy Phenotype of ABCA4 Disease. Ophthalmology 125:89-99
Duncker, Tobias; Lee, Winston; Jiang, Fan et al. (2018) ACUTE ZONAL OCCULT OUTER RETINOPATHY: Structural and Functional Analysis Across the Transition Zone Between Healthy and Diseased Retina. Retina 38:118-127
Paavo, Maarjaliis; Zhao, Jin; Kim, Hye Jin et al. (2018) Mutations in GPR143/OA1 and ABCA4 Inform Interpretations of Short-Wavelength and Near-Infrared Fundus Autofluorescence. Invest Ophthalmol Vis Sci 59:2459-2469
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Paavo, Maarjaliis; Lee, Winston; Merriam, John et al. (2017) Intraretinal Correlates of Reticular Pseudodrusen Revealed by Autofluorescence and En Face OCT. Invest Ophthalmol Vis Sci 58:4769-4777
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Zernant, Jana; Lee, Winston; Collison, Frederick T et al. (2017) Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. J Med Genet 54:404-412

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