Retinal pigment epithelial (RPE) cells of the eye amass bisretinoid fluorophores with age. This group of pigments, including the founding member A2E, forms in photoreceptor cells due to inadvertent reactions of retinaldehyde. They are deposited in RPE within phagocytosed outer segment membrane and they accumulate as lipofuscin. The damaging effects of these compounds on RPE cells are implicated in a number of age-associated and early-onset forms of macular disease including recessive Stargardt disease, ELOVL4-related disease, best macular dystrophy and age-related macular degeneration. The broad objectives of the studies proposed in this application are to understand mechanisms by which bisretinoids of retina contribute to disease processes that threaten vision. We will address both the bisretinoid pigments constituting RPE lipofuscin and the bisretinoid precursors of these compounds in photoreceptor cells. This work will elucidate therapeutic avenues. Additionally since bisretinoids are the major source of fundus autofluorescence, these studies will contribute to clinical interpretations of fundus autofluorescence images.
In Specific Aim 1, we will investigate our preliminary observation that photo-cleavage of bisretinoid releases the small dicarbonyls (methylglyoxal and glyoxal) that are responsible for advanced glycation end-product (AGE) - modifications of proteins. Proteins in Bruch's membrane and drusen are prone to AGE-modification. Aging changes in Bruch's membrane are also considered to contribute to onset of age-related macular degeneration. We propose that, unlike the case in diabetes, AGE-adducts in Bruch's membrane form as a consequence of dicarbonyl release from overlying RPE.
In Specific Aim 2, we will probe for evidence of photooxidation-associated photodegradation of RPE bisretinoid in vivo.
In Specific Aim 3 we will explore the bisretinoid fluorophores located in photoreceptor cell outer segments that are precursors of RPE lipofuscin. We will probe the propensity for increased formation of bisretinoid in impaired photoreceptor cells;we will test the ability of photoreceptor bisretinoids to mediate oxidation of lipid in photoreceptor cells and photo-damage;and we will demonstrate conditions under which photoreceptor bisretinoids can contribute to hyperautofluorescence in fundus autofluorescence images.
These aims will be achieved by the use of animal and in vitro models and by employing biochemical and histological approaches. Completion of this research will advance our comprehension of drusen formation and will elucidate links between RPE lipofuscin and the aging changes in Bruch's membrane that can be a prelude to AMD. These studies will contribute to an understanding of how light and oxidative mechanisms are factors in photoreceptor cell death in monogenic 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 in the application will address disease mechanisms that may be influential in early onset and age-related macular degeneration and in some forms of retinitis pigmentosa;therapeutic avenues are addressed.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY012951-13
Application #
8511140
Study Section
Special Emphasis Panel (BVS)
Program Officer
Shen, Grace L
Project Start
2000-05-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
13
Fiscal Year
2013
Total Cost
$490,349
Indirect Cost
$183,881
Name
Columbia University (N.Y.)
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Sparrow, Janet R (2016) Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics. Proc Natl Acad Sci U S A 113:4564-9
Ueda, Keiko; Zhao, Jin; Kim, Hye Jin et al. (2016) Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration. Proc Natl Acad Sci U S A 113:6904-9
Liu, Zhao; Ueda, Keiko; Kim, Hye Jin et al. (2015) Photobleaching and Fluorescence Recovery of RPE Bisretinoids. PLoS One 10:e0138081
Zhou, Jilin; Ueda, Keiko; Zhao, Jin et al. (2015) Correlations between Photodegradation of Bisretinoid Constituents of Retina and Dicarbonyl Adduct Deposition. J Biol Chem 290:27215-27
Wu, Li; Ueda, Keiko; Nagasaki, Taka et al. (2014) Light damage in Abca4 and Rpe65rd12 mice. Invest Ophthalmol Vis Sci 55:1910-8
Yang, Jin; Li, Yao; Chan, Lawrence et al. (2014) Validation of genome-wide association study (GWAS)-identified disease risk alleles with patient-specific stem cell lines. Hum Mol Genet 23:3445-55
Sparrow, Janet R; Duncker, Tobias (2014) Fundus Autofluorescence and RPE Lipofuscin in Age-Related Macular Degeneration. J Clin Med 3:1302-21
Flynn, Erin; Ueda, Keiko; Auran, Emily et al. (2014) Fundus autofluorescence and photoreceptor cell rosettes in mouse models. Invest Ophthalmol Vis Sci 55:5643-52
Sparrow, Janet R; Zhou, Jilin; Ghosh, Shanti Kaligotla et al. (2014) Bisretinoid degradation and the ubiquitin-proteasome system. Adv Exp Med Biol 801:593-600
Liu, Zhenzhen; Qin, Tingyu; Zhou, Jilin et al. (2014) Impairment of the ubiquitin-proteasome pathway in RPE alters the expression of inflammation related genes. Adv Exp Med Biol 801:237-50

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