September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Role of the Fas death receptor in light-damage induced photoreceptor degeneration
Author Affiliations & Notes
  • Edward Linton
    Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Chenguang Wang
    The Second Hospital of Jilin University, Changchun, China
  • Delu Song
    Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Liangliang Zhao
    The Second Hospital of Jilin University, Changchun, China
  • Ying Song
    Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Jeff Jamison
    ONL Therapeutics, Ann Arbor, Michigan, United States
  • John Freshley
    ONL Therapeutics, Ann Arbor, Michigan, United States
  • David N Zacks
    Ophthalmology, Univ of Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan, United States
  • Joshua L Dunaief
    Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Edward Linton, None; Chenguang Wang, None; Delu Song, None; Liangliang Zhao, None; Ying Song, None; Jeff Jamison, ONL Therapeutics (E); John Freshley, ONL Therapeutics (E); David Zacks, None; Joshua Dunaief, ONL Therapeutics (F)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5797. doi:
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    • Get Citation

      Edward Linton, Chenguang Wang, Delu Song, Liangliang Zhao, Ying Song, Jeff Jamison, John Freshley, David N Zacks, Joshua L Dunaief; Role of the Fas death receptor in light-damage induced photoreceptor degeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5797.

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

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Abstract

Purpose : The death receptor Fas, activator of the apoptosis extrinsic pathway, is expressed at higher levels in AMD retinas compared with aged matched controls.1 A small molecule Fas inhibitor has been shown to reduce cell death in a rodent model of retinal detachment.2 Here, we tested whether photoreceptor cell death in the mouse and rat light damage (LD) model involves Fas-activation.

1 Dunaief et al. The Role of Apoptosis in Macular Degeneration. Arch Oph 2003
2 Besirli et al. Inhibition of Retinal Detachment-Induced Apoptosis in Photoreceptors by a Small Peptide Inhibitor of the Fas Receptor. IOVS 2010.

Methods : 2-3mo Balb/c mice and Sprague Dawley rats were used in the LD model. Mice were placed in a light box and exposed to 10,000lux of white LED light for 4h, from 12-4pm. Rats were exposed to 1.9-2.2kft-c, fluorescent light 420 to 485 nm with 25 nm half max width light for 6 hours and 8 hours from 8am-2/4pm with control animals being exposed to no light. Mice had no prior dark adaptation while rats were dark adapted overnight. All rodents were euthanized 24h after the initiation of light exposure. Control rodents were maintained under normal 12h light cycle conditions, with no light damage (NLD). After euthanasia, eyes were used for Fas immunolabeling, TUNEL, and qPCR for levels of Fas, Fas ligand, Rho, Rpe65, and iron homeostasis genes Cp and Ho-1. One-way ANOVA was used for statistical analysis. Some mice were injected with Fas inhibitor peptide in one eye and saline vehicle in the other 4 days before LD. Photoreceptor degeneration after LD was assessed with OCT.

Results : LD caused a significant increase in Fas mRNA (p=.0163) and an increase in TUNEL and Fas immunolabeling (p<.0001) in the superior retina compared with NLD controls. Iba-1 (a microglia/macrophage marker) and Fas-L co-labeling showed an increase in infiltration of microglia expressing FasL into the ONL following LD compared with NLD controls. LD did not increase FasL mRNA levels (p=.54), but did increase levels of Cp (p<.0001), Hmox1 (p<.02) and decreased Rho (p<.01). OCT revealed a decrease in ONL thickness after LD that was partially rescued by pre-treatment with a Fas inhibitor.

Conclusions : Our results are consistent with the hypothesis that the LD model of retinal degeneration causes photoreceptor cell death and retinal degeneration, in part, through Fas activation. Further work will optimize the formulation and delivery of Fas inhibitors.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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