Janet R. Sparrow, PhD

Our Providers

Academic Appointments

  • Anthony Donn Professor of Ophthalmic Science (in Ophthalmology)
  • Professor of Pathology & Cell Biology
Janet R. Sparrow, PhD

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.

Email: jrs88@cumc.columbia.edu

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.

Lab Locations

  • CUIMC/Edward S. Harkness Eye Institute Research Annex

    160 Fort Washington Ave
    7th Floor, Room 701
    New York, NY 10032
    Phone:
    (212) 305-9944
    Fax:
    (212) 305-9638
    Email:
    jrs88@columbia.edu

Honors and 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

Research Interests

  • Development of therapies to limit RPE lipofuscin formation
  • Interpretation of patterns of fundus autofluorescence in retinal disorders
  • Investigating links between RPE lipofuscin and drusen formation in age-related macular degeneration
  • Quantitation of fundus autofluorescence intensities
  • Understanding the composition of RPE bisretinoid lipofuscin and conditions modulating its formation

NIH Grants

  • THERAPEUTIC GENE EDITING AND MULTIMODAL IMAGING IN JUVENILE MACULAR DEGENERATION (Federal Gov)

    Jun 1 2020 - May 31 2025

    INTEGRATED ANALYSIS OF GENETIC AND CLINICAL DATA FOR RATIONAL CLINICAL TRIALS OF STARGARDT DISEASE (Private)

    Dec 1 2018 - Nov 30 2023

    RETINAL DISEASE PROMOTED BY IRON-INDUCED BISRETINOID OXIDATION (Federal Gov)

    Apr 1 2018 - Jan 31 2023

    TRANSLATIONAL GENE THERAPY FOR CNGB1 RETINITIS PIGMENTOSA (Federal Gov)

    Apr 1 2018 - Jan 31 2023

    QUANTITATIVE FUNDUS AUTOFLUORESCENCE IN RETINAL DISORDERS (Federal Gov)

    Mar 1 2019 - Dec 31 2022

    STARGARDT DISEASE WITH LOW LIPOFUSCIN (Federal Gov)

    Mar 1 2019 - Dec 31 2022

    QUANTITATIVE FUNDUS AUTOFLUORESCENCE (P&S Industry Clinical Trial)

    May 29 2017 - May 29 2022

    IMPACT OF LIPOFUSCIN IN RETINAL PIGMENT EPITHELIAL CELLS (Federal Gov)

    Sep 1 2017 - Jun 30 2021

    IMPACT OF LIPOFUSCIN IN RETINAL PIGMENT EPITHELIAL CELLS (Federal Gov)

    Sep 30 2017 - Jun 30 2020

    QUANTITATIVE FUNDUS AUTOFLUORESCENCE IN RETINAL DISORDERS (Federal Gov)

    Jun 1 2014 - May 31 2019

    QUANTITATIVE FUNDUS AUTOFLUORESCENCE IN RETINAL DISORDERS (Federal Gov)

    Jun 1 2014 - May 31 2018

    QUANTITATIVE FUNDUS AUTOFLUORESCENCE IN RETINAL DISORDERS (Federal Gov)

    Jun 1 2014 - May 31 2018

    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

    IMPACT OF LIPOFUSCIN IN RETINAL PIGMENT EPITHELIAL CELLS (Federal Gov)

    May 1 2000 - Aug 31 2017

    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

    GREATER NEW YORK REGINAL RESEARCH CENTER FOR THE STUDY OF RETINAL DEGENERATIVE (Private)

    Jul 1 2010 - Jun 30 2015

    HUTCIN 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 C ELLS (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

    BIOMEDICAL IMAGE ENGINEERING OF MACULAR IMAGES (Federal Gov)

    Sep 15 2005 - Aug 31 2010

Lab Members

  • Keiko Ueda, PhD, Associate Research Scientist
  • Jin Zhao, PhD, Associate Research Scientist
  • Hyejin Kim, PhD, Postdoctoral Research Scientist
  • Paavo Maarjaliis, MD, Postdoctoral Research Scientist
  • John Peregin, B.S.,