- Anthony Donn Professor of Ophthalmic Sciences (in Ophthalmology)
- Professor of Pathology & Cell Biology
Work in the laboratory is aimed at examining a causal link between the intracellular accumulation of lipofuscin fluorophores and retinal pigmented epithelial (RPE) cell death. We have shown that a major fluorophore of RPE lipofuscin, A2E, confers a susceptibilty to blue light-mediated cell death and can lead to a detergent-like perturbation of membranes. We are also examining mechanisms involved in A2E biosynthesis and conditions under which the formation of A2E may be accelerated. The death of RPE cells in several retinal disorders including Stargardt's disease and atrophic age-related macular degeneration (AMD), precedes the degeneration of photoreceptor cells and the impairment of vision. A major focus of work in the laboratory involves studies of a causal link between the intracellular accumulation of aging pigments (lipofuscin) in the RPE and the death of those cells. A major hydrophobic constituent of RPE lipofuscin is the fluorophore A2E, a bis-retinoid whose biosynthesis begins randomly in photoreceptor cell outer segments. A2E is generated from the precursor A2-PE after phosphate hydrolysis, it is deposited in RPE cells secondary to phagocytosis of shed outer segment membrane and it accumulates as lipofuscin because it cannot be degraded by RPE lysosomal enzymes. Light is also involved in mechanisms that lead to the atrophy of A2E-laden RPE. Thus, accumulation of A2E in the lysosomal compartment of the cultured RPE confers a susceptibilty to blue light-mediated cell death; the wavelength dependency of this effect is consistent with the excitation spectra of A2E and with the known susceptibility of RPE cells to blue light damage in animal models. The cell death program which is initiated by blue light illumination of A2E involves the activation of caspase-3 a downstream cysteine-dependent protease and is regulated by Bcl-2 an anti-apoptotic protein situated in the outer mitochondrial membrane. Evidence indicates that the generation of singlet oxygen upon photoexcitation of A2E is integral to the death of the cells. In particular singlet oxygen which is generated by photosensitization of A2E becomes inserted into carbon-carbon double bonds of the retinoid-side arms of A2E to generate highly reactive epoxides. Since the considerable ring strain and electrophilicity of these three-membered oxygen and carbon containing rings makes them susceptible to reaction with nucleophilic macromolecules such as DNA and protein, A2E-epoxides may be agents that ravage the cell. Indeed, we have shown that at least one of the subcellular structures damaged by A2E-epoxides, is DNA with guanine bases of DNA being oxidatively modified to generate 8-oxo-dG and perhaps other structurally related lesions. In other experiments, A2E-epoxides have been shown to generate products of lipid peroxidation in RPE cells. The mediation of light damage may not be the only mechanism by which A2E induces cell injury, since A2E can also mediate a detergent-like perturbation of cell membranes. The structure of A2E, both its possession of hydrophobic and hydrophilic domains and its wedge-shaped configuration, is central to this property. These studies are relevant to the non-neovascular, atrophic form of age-related macular degeneration that accounts for up to 21% of the visual loss associated with AMD and that is characterized by a massive accumulation of lipofuscin preceding RPE cell death. These observations also revive the unresolved issue of whether lifelong exposure to bright light contributes to AMD.
Vitamin A aldehyde-conjugates accumulate as lipofuscin in retinal pigment epithelial (RPE) cells and have been linked to disease processes in some inherited forms of macular degeneration as well as age-related macular degeneration. These bisretinoid constituents of lipofuscin are unique to RPE and in addition to A2E include all-trans-retinal dimer and its conjugates, phosphatidyl-dihydropyridine bisretinoid (A2-DHP-PE) and a conjugate of all-trans-retinal and glycerophosphoethanolamine (A2-GPE). The excitation and emission spectra of these compounds can also account for the inherent autofluorescence of the retina (fundus autofluorescence).
Dr. Sparrow’s laboratory has shown that the adverse effects of RPE lipofuscin pigments are attributable, at least in part, to their detergent-like structure and their photo-sensitive properties. In the latter case, bisretinoids can generate reactive forms of oxygen; they also undergo photooxidation and photodegradation. The photo-cleavage products of A2E consists of a complex mixture of aldehyde-bearing fragments that includes the small dicarbonyls methylglyoxal and glyoxal that are responsible for damaging modifications of proteins – advanced glycation end-products (AGEs). AGE-modified proteins are present in drusen. We are applying our understanding of RPE bisretinoids to clinical interpretations and measurements of fundus autofluorescence. Taken together work in the laboratory contributes to the elucidation of pathology in several retinal disorders including recessive Stargardt disease, retinitis pigmentosa, pattern dystrophies and age-related macular degeneration.
Therapeutic strategies her laboratory investigates to target bisretinoids include antioxidants, inhibitors of complement activation, small molecules that inhibit their formation and gene-based therapy.
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Edward S. Harkness Eye Institute Research Annex160 Fort Washington Avenue
7th Floor, Room 701
New York, NY 10032
- (212) 305-9944
- (212) 305-9638
Honors & Awards
- Province of Ontario Graduate Scholarship
- Collip Medal, University of Western Ontario
- National Multiple Sclerosis Society Postdoctoral Fellowship
- National Institutes of Health Postdoctoral Fellowship
- Lew R. Wasserman Merit Award, Research to Prevent Blindness
- Alcon Research Institute Award
- Research to Prevent Blindness Senior Scientific Investigator Award
- Understanding the composition of RPE bisretinoid lipofuscin and conditions modulating its formation
- Investigating links between RPE lipofuscin and drusen formation in age-related macular degeneration
- Development of therapies to limit RPE lipofuscin formation
- Interpretation of patterns of fundus autofluorescence in retinal disorders
- Quantitation of fundus autofluorescence intensities
QUANTITATIVE FUNDUS AUTOFLUORESCENCE IN RETINAL DISORDERS (Federal Gov)
Jun 1 2014 - May 31 2018
IMPACT OF LIPOFUSCIN IN RETINAL PIGMENT EPITHELIAL CELLS (Federal Gov)
May 1 2000 - Aug 31 2017
THERAPEUTIC APPROACHES FOR ABCA4-ASSOCIATED DISORDERS (Federal Gov)
Aug 1 2011 - Jul 31 2017
RETINAL MECHANISMS (Federal Gov)
Apr 1 2012 - Mar 31 2016
HUTC IN THE ROLE OF RPE LIPOFUSCIN, AND A2E COMPLEMENT DYSREGULATION IN AGE-RELATED MACULAR DEGENERATION (Private)
Mar 21 2013 - Sep 30 2014
FUNCTIONAL ANALYSES OF EMBRYONIC STEM CELL DERIVED RETINAL CELLS (NY State Gov)
Sep 1 2010 - Aug 31 2014
QUANTITATIVE FUNDUS AUTOFLUORESCENCE AND CORRELATIONS WITH GENOTYPE IN AGE RELATED MACULAR DEGENERATION (Private)
Jul 1 2013 - Jun 30 2014
LIMITING RPE LIPOSUSCIN ACCUMULATION BY HARNESSING ENZYME MEDIATED DEGRADATION (Private)
Dec 15 2009 - Sep 30 2013
TESTING VARIOUS CHROMOPHORES FOR USE IN IOLS: PROTECTION AGA INST 430 NM DAMAGE TO RPE CELLS THAT HAV (Private)
Apr 1 2010 - Mar 31 2012
RETINAL MECHANISMS AND VISUAL RESOLUTION (SUBCONTRACT WITH THE UNIVERISITY OF ROCHESTER) (Federal Gov)
Jan 1 2009 - Dec 31 2011
EFFICACY OF FACTOR H PREPARATIONS (Private)
Jan 17 2011 - Dec 14 2011
TOWARDS THERAPEUTIC DISCOVERY FOR MACULAR DEGENERATION (Private)
Dec 1 2010 - Aug 31 2011
INVESTIGATING INHIBITORS OF RPE LIPOFUSCIN FORMATION (Private)
Dec 1 2006 - Dec 31 2010
- Jilin Zhou, MD, Associate Research Scientist
- Keiko Ueda, PhD, Postdoctoral Research Scientist
- Zhao Llu, PhD, Postdoctoral Research Scientist
- Heike Schoenherr, PhD, Postdoctoral Research Scientist
- Erin Flynn, BS
- Janice David
Duncker T, Tabacaru MR, Lee W, Tsang SH, Sparrow JR, Greenstein VC. 2013. Comparison of near-infrared and short-wavelength autofluorescence in retinitis pigmentosa. Invest Ophthalmol Vis Sci 17:585-591.
Dobri N, Quin Q, Kong J, Yamamoto K, Liu Z, Moiseyev G, Ma JX, Allikmets R, Sparrow JR, Petrukhin K. 2013. A1120, a non-retinoid RBP4 antagonist inhibits formation of cytotoxic bisretinoids in an animal model of enhanced retinal lipofuscinogenesis. Invest Ophthalmol 7:85-95.
Gelman R, Chen R, Blonska A, Barile G, Sparrow JR. 2012. Fundus autofluorescence imaging in a patient with rapidly developing scotoma. Retinal Cases & Brief Reports 6:345-348.
Sparrow JR, Gregory-Roberts E, Yamamoto K, Blonska A, Ghosh SK, Ueda K, Zhou J. 2012. The bisretinoids of retinal pigment epithelium. Prog Retin Eye Res 31:121-135.
Yamamoto K, Zhou J, Hunter JJ, Williams DR, Sparrow JR. 2012. Toward an understanding of bisretinoid autofluorescence bleaching and recovery. Invest Ophthalmol Vis Sci 53:3536-3544.
Delori F. Greenberg JP, Woods RL, Fischer J, Bruncker T, Sparrow JR, Smith RT. 2012. Quantitative measurements of autofluorescence with the scanning laser ophthalmoscope. Invest Ophthalmol Vis Sci 52:9379-9390.
Wu Y, Zhou J, Fishkin N, Rittman B.E. Sparrow JR. 2011. Enzymatic degradation of A2E, an RPE lipofuscin bisretinoid. Journal American Chemical Society 133:849-857.
Yamamoto K, Yoon KD, Ueda K, Hashimoto M, Sparrow JR. 2011. A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine. Invest Ophthalmol Vis Sci 52:9084-9090.
Wu Y, Yanase E, Feng X, Siegel MM, Sparrow JR. 2010. Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration. Proc Natl Acad Sci 107:7275-7280.
Sparrow JR, Yoon K, Wu Y, Yamamoto K. 2010. Interpretations of fundus autofluorescence from studies of the bisretinoids of retina. Invest Ophthalmol Vis Sci 51:4351-4357 (by invitation).
Chrispell JD, Feathers KL, Kane MA, Kim CY, Brooks M, Khanna R, Kurth I, Huebner CA, Gal A, Mears AJ, Swaroop A, Napoli JL, Sparrow JR, Thompson DA. RDH12. 2009. Activity and Effects on Retinoid Processing in the Murine Retina. J Biol Chem 284: 21468-21477.
Wu Y, Fishkin NE, Pande A, Pande J and Sparrow JR. 2009. A novel lipofuscin bisretinoid prominent in human retina and in a model of recessive Stargardt disease. J Biol Chem J Biol Chem 284:21468-21477
Ng KP, Gugiu BG, Renganathan K, Davies MW, Gu X, Crabb JS, Kim SR, Rozanowska MB, Bonilha VL, Rayborn ME, Salomon RG, Sparrow JR, Boulton ME, Hollyfield JG, Crabb JW. 2008. Retinal pigment epithelium lipofuscin proteomics. Mol Cell Proteomics. 7:1397-1405.
Kong J, Kim SR, Binley K, Pata I, Doi K, Mannik J, Zernant-Rajang J, Kan O, Iqball S, Naylor S, Sparrow JR, Gouras P, Allikmets R. 2008. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Therapy 15:1311-1320.
Kim SR, Jang YP, Jockusch S, Fishkin NE, Turro NJ, Sparrow JR. 2007. The all-trans-retinal dimer-series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model. Proc Natl Acad Sci U S A 104:19273-19278.
Zhou J, Jang YP, Kim SR, Sparrow JR. 2006. Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci 103:16182-16187.
Maiti, P, Kong J, Kim SR, Sparrow JR, Alllikmets R and Rando RR. 2006. Small molecule RPE65 antagonists limit the visual cycle and prevent lipofuscin formation. Biochemistry 45:852-860