July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Mice with RPE-specific CLIC4 deficiency exhibit AMD-like changes in the retina-RPE-choroid complex
Author Affiliations & Notes
  • Wataru Otsu
    Dyson Vision Research Institute, Weill Cornell Medical College, New York, New York, United States
  • Kuo-Shun Hsu
    Dyson Vision Research Institute, Weill Cornell Medical College, New York, New York, United States
  • Joshua L Dunaief
    Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Yao Li
    Department of Ophthalmology, Columbia University, New York, New York, United States
  • Stephen H. Tsang
    Department of Ophthalmology, Columbia University, New York, New York, United States
  • Jen-Zen Chuang
    Dyson Vision Research Institute, Weill Cornell Medical College, New York, New York, United States
  • Ching-Hwa Sung
    Dyson Vision Research Institute, Weill Cornell Medical College, New York, New York, United States
  • Footnotes
    Commercial Relationships   Wataru Otsu, None; Kuo-Shun Hsu, None; Joshua Dunaief, None; Yao Li, None; Stephen Tsang, None; Jen-Zen Chuang, None; Ching-Hwa Sung, None
  • Footnotes
    Support  NIH EY016805, RPB, Banflok
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1229. doi:https://doi.org/
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      Wataru Otsu, Kuo-Shun Hsu, Joshua L Dunaief, Yao Li, Stephen H. Tsang, Jen-Zen Chuang, Ching-Hwa Sung; Mice with RPE-specific CLIC4 deficiency exhibit AMD-like changes in the retina-RPE-choroid complex. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1229. doi: https://doi.org/.

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

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Abstract

Purpose : Chloride intracellular channel protein 4 (CLIC4) has a pleiotropic role in several cellular processes (oxidative stress, inflammation, lipid metabolism, extracellular matrix remodeling) that are known to be the risk factors for age-related macular degeneration (AMD). We asked whether deleting the gene encoding CLIC4 in the retinal pigment epithelial (RPE) cells (i.e., the primary lesion site of the AMD) is sufficient to trigger the AMD-like retinal pathophysiology.

Methods : We generated the RPE-specific CLIC4 knockout mice (Best1-Cre: CLIC4f/f mice in the rd8-free, B6/J background). We performed several assays, including the fundus imaging, optical coherence tomography, indocyanine green angiography, electroretinogram, (immuno)histochemistry, and 3D electron microscopy (focused ion beam scanning EM), to comprehensively depict the retinal pathology of the mutant mice. The age-matched control counterparts were also assayed in parallel. For the mechanistic studies, we generated the human RPE monolayers that stably expressed the doxycycline-induced CLIC4-shRNA.

Results : Young adult (3-9-month-old) CLIC4 mutant mice showed several retinal defects resembling those seen in the human AMD patients. These include microvillar atrophy, basolateral lipid accumulation, Bruch’s membrane/choroidal abnormality, and declined visual functions. We optimized the condition to acutely knock down the CLIC4 in polarized human RPE monolayers. We are currently investigating the biochemical and cellular properties altered by the silencing of CLIC4 in the RPE monolayers.

Conclusions : The RPE-expressed CLIC4 critically regulates the homeostasis of the retina-RPE-chloroid complex. The early-onset phenotypic manifestation suggests that the CLIC4 mutant mice represent a novel model for investigating AMD-associated phenotypes without the ambiguity of “senescence-alone” effect. The genetically modified human RPE monolayers we generated are also a novel platform to decipher the function of RPE-expressed CLIC4.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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