July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Genetic deficiency of nuclear receptor REV-ERBα causes retinal pigment epithelial cell degeneration in mice
Author Affiliations & Notes
  • Shuo Huang
    Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Chi-Hsiu Liu
    Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Zhongxiao Wang
    Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Ye Sun
    Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Zhongjie Fu
    Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Rubi Duran
    Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Alexander Poblete
    Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Steve S Cho
    Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Jing Chen
    Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Shuo Huang, None; Chi-Hsiu Liu, None; Zhongxiao Wang, None; Ye Sun, None; Zhongjie Fu, None; Rubi Duran, None; Alexander Poblete, None; Steve Cho, None; Jing Chen, None
  • Footnotes
    Support  This work was supported by NIH/NEI (R01 EY024963 and R01 028100), BrightFocus Foundation and Research to Prevent Blindness (to JC)
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2452. doi:
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      Shuo Huang, Chi-Hsiu Liu, Zhongxiao Wang, Ye Sun, Zhongjie Fu, Rubi Duran, Alexander Poblete, Steve S Cho, Jing Chen; Genetic deficiency of nuclear receptor REV-ERBα causes retinal pigment epithelial cell degeneration in mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2452.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Oxidative damage-induced retinal pigment epithelium (RPE) dysfunction and atrophy contribute to the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. REV-ERBα is a redox (reduction/oxidation) -sensing nuclear receptor and transcription repressor that regulates circadian control and cell metabolism, yet its function in the eye is not clear. In this project we investigated the role of REV-ERBα in the regulation of RPE metabolism and degeneration in mice genetically deficient of REV-ERBα.

Methods : REV-ERBα deficient (Rev-erbα-/-) mice and littermate wild type (WT) controls were analyzed at various time points during aging. Morphological features were analyzed with in vivo fundus imaging and in isolated RPE/choroid complex flat mounts and cross-sections from enucleated eyes. Visual function was evaluated with electroretinography. Expression levels of Rev-erbα and relevant metabolic and inflammatory genes were analyzed in RPE isolated from Rev-erbα-/- and WT mice.

Results : REV-ERBα was expressed in RPE in WT eyes. Deficiency of REV-ERBα in aged mouse eyes caused abnormal subretinal lesions in fundus imaging, and patchy areas of RPE degeneration with disrupted cell junction in RPE/choroidal flat mounts and cross sections. ERG analysis of aging mice revealed substantial decrease in both a- and b-waves, indicating deficits in retinal visual function. In addition, Rev-erbα-/- RPE showed decreased expression of tight junction genes (ZO-1, Ocln and Clnd5), consistent with junctional disruption. Substantial decrease in cell metabolic genes and increased expression of inflammatory genes were also found in Rev-erbα-/- RPE.

Conclusions : Together these findings suggest that REV-ERBα is a novel transcriptional regulator of RPE function in AMD pathogenesis and a potential target for future therapeutics.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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