Research Faculty

Address
635 West 168th Street
Harkness Eye Institute, Room 701
New York, NY 10032

Phone: 212-305-9944
Fax: 212-305-9638

jrs88@columbia.edu
Janet Sparrow, Ph.D.
Anthony Donn Professor of Ophthalmic Science and Pathology and Cell Biology
Research Summary

Vitamin A aldehyde-derived compounds accumulate as lipofuscin in retinal pigment epithelial (RPE) cells with age and have been linked to recessive Stargardt disease, dominant Stargardt-like maculopathy, Best vitelliform macular degeneration and age-related macular degeneration. Our research in this area is directed toward understanding the composition of RPE lipofuscin, the properties of the constitutents of this material, mechanisms by which they form and the adverse effects of these compounds on retina. We work with in vitro and animal models to understand the role of RPE lipofuscin in retinal degenerative disorders, to elucidate conditions that augment the formation of RPE lipofuscin and to investigate RPE lipofuscin pigments as therapeutic targets. Since the bisretinoids of retina are the source of fundus autofluorescence our work also aims to apply an understanding of RPE bisretinoids to clinical interpretations and measurements of fundus autofluorescence in retinal disease.

The bisretinoid constituents of lipofuscin are likely unique to RPE and in addition to A2E include all-trans-retinal dimer series of compounds (all-trans-retinal dimer, all-trans-retinal dimer-phosphatidylethanolamine, all-trans-retinal dimer-ethanolamine) and A2-DHP-PE, a phosphatidyl-dihydropyridine bisretinoid and A2-GPE. For these bischromophores, absorbance maxima in the visible spectrum are conferred by systems of conjugated double bonds extending along the arms of the molecules and into the six-membered rings. The excitation and emission spectra of these compounds also account for fundus autofluorescence.

We have shown that the adverse effects of RPE lipofuscin pigments are attributable, at least in part, to their detergent-like structure, their ability to initiate photooxidative processes and in some cases their tendency to undergo pH dependent protonation/deprotonation. Given that AMD pathogenesis has been linked to variants in the genes encoding complement factors it is potentially significant that the bisretinoid compounds of RPE lipofuscin can also activate complement.
Selected Publications

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.

Allocca M, Doria M, Petrillo M, Colella P, Garcia-Hoyos M, Gibbs D, Kim SR, Maguire A, Rex TS, Vicino, UD, Sparrow JR, Williams DS, Bennett J, Auricchio, A. 2008. Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective in vivo gene delivery. J Clin Investigation 118: 1955-64.

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 284:21468-21477.

Zhou J, Kim SR, Westlund B, Sparrow JR. 2009. Complement activation by bisretinoid constituents of RPE lipofuscin. Invest Ophthalmol Vis Sci 50:1392-1399.

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.

Secondi R, Kong J, Blonska A, Staurenghi G, Sparrow JR. 2012. Fundus autofluorescence findings in a mouse model of retinal detachment. Invest Ophthalmol Vis Sci 53:5190-5197. PMCID:PMC3416030

Sparrow JR, Blonska A, Flynn E, Duncker T, Greenberg JP, Secondi R, Ueda K, Delori FC. 2013. Quantitative fundus autofluorescence in mice. Correlation with HPLC quantitation of RPE lipofuscin and measurement of retinal outer nuclear layer. Invest Ophthalmol Vis Sci. 54:2812-2820.
Honors and Awards

Lew R. Wasserman Merit Award, Research to Prevent Blindness, 2001

Alcon Research Institute Award, 2004 (a prestigious award in ophthalmic research; given yearly to exceptional researchers in ophthalmology and visual science)

Research to Prevent Blindness Senior Scientific Investigator Award, 2007

ARVO Fellow
Committees , Council, and Professional Society Memberships

NIH-NEI DPVS Regular member, 2009-2013
Keywords

Retina, retinal pigment epithelium, bisretinoid, lipofuscin, retinal degeneration, maculopathy; fundus autofluorescence


top
 
 
Contact the Pathology Webmaster at PathWebMaster@columbia.edu