July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Gene regulation dynamics induced by the protein kinase inhibitor, SBJ-051 associated with neuroprotection in light-induced photoreceptor cell death
Author Affiliations & Notes
  • Byung-Jin Kim
    The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • Jie Wang
    The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • Tomohiro Masuda
    The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • Melissa Liu
    The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • Reji Nair
    Chemistry, The Scripps Research Institute-FL, Jupiter, Florida, United States
  • Jiang Qian
    The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • Derek Stuart Welsbie
    Shiley Eye Institute, UC San Diego, San Diego, California, United States
  • Thomas Bannister
    Chemistry, The Scripps Research Institute-FL, Jupiter, Florida, United States
  • Timothy Spicer
    Molecular Medicine, The Scripps Research Institute-FL, Jupiter, Florida, United States
  • Louis Scampavia
    Molecular Medicine, The Scripps Research Institute-FL, Jupiter, Florida, United States
  • George Trainor
    BioMotiv, Cleveland, Ohio, United States
  • Amy Trainor
    BioMotiv, Cleveland, Ohio, United States
  • Donald J Zack
    The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Byung-Jin Kim, None; Jie Wang, None; Tomohiro Masuda, None; Melissa Liu, None; Reji Nair, None; Jiang Qian, None; Derek Welsbie, None; Thomas Bannister, None; Timothy Spicer, None; Louis Scampavia, None; George Trainor, None; Amy Trainor, None; Donald Zack, BioMotiv (F), Johns Hopkins University (P)
  • Footnotes
    Support  NEI, R01EY001919, NEI, P30EY002162 (MML), NEI, T32EY007143,Research to Prevent Blindness, Foundation Fighting Blindness, BrightFocus, BioMotiv, Guerrieri Family Foundation
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 4863. doi:https://doi.org/
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Byung-Jin Kim, Jie Wang, Tomohiro Masuda, Melissa Liu, Reji Nair, Jiang Qian, Derek Stuart Welsbie, Thomas Bannister, Timothy Spicer, Louis Scampavia, George Trainor, Amy Trainor, Donald J Zack; Gene regulation dynamics induced by the protein kinase inhibitor, SBJ-051 associated with neuroprotection in light-induced photoreceptor cell death. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4863. doi: https://doi.org/.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Protein kinase-associated signaling pathways have been implicated as important modulators of retinal cell survival and functional integrity. We tested the potential protective effects of the multi-targeted kinase inhibitors SBJ-051 and sunitinib on photoreceptor (PR) degeneration in the murine light-damage (LD) model and identified gene profiles associated with SBJ-051-induced PR protection.

Methods : Female BALB/cJ mice (12wk) were administered SBJ-051 (10 mg/kg), sunitinib (60 mg/kg), or vehicle (5% DMSO) by daily intraperitoneal injection starting 72 h prior to LD and continuing up to 6 days post LD. Serial SD-OCT imaging, immunohistochemistry, and scotopic ERG were performed to assess retinal structure and function after 4h light-induced retinal damages (~3000 lux). cDNA libraries were generated using total retinal RNA collected at various time points after LD (0, 3, 6, 12 h) from vehicle and SBJ-051-treated experimental groups, and RNAseq analysis was performed.

Results : Administration of SBJ-051 at 10 mg/kg and sunitinib at 60 mg/kg induced significant protection against LD-induced total retinal outer layers (ROL) thinning compared to vehicle treated animals - degeneration in the ROL (44.78 ± 0.03%, P<0.001) was associated with a decrease in ERG amplitudes (a-wave, 89.99 ± 4.99%, P<0.01, and b-wave, 75.61 ± 6.94%, P<0.01) and changes of cellular markers in response to LD, whereas administration of SBJ-051 and sunitinib protected retinal thinning with no significant differences with vehicle group. RNAseq analysis of samples obtained immediately post LD (0 h) showed upregulation of 780 genes and downregulation of 597 genes, with additional gene expression dynamics evident at later time points. Analysis of SBJ-051 treated animals identified a number of genes that were differentially regulated compared to vehicle treated animals, including rep65, crytallin genes, cfh, fos, and other inflammatory genes based on our analysis with fold change > 1.5 and Fdr < 0.1

Conclusions : Our data demonstrates that SBJ-051 (10 mg/kg) and sunitinib (60 mg/kg) promote PR survival after LD and lead to a limited number of gene expression changes, some of which appear to be associated with key signaling pathways such as TNF signaling pathway. Further analysis of these gene expression changes and the potentially affected signaling pathways is currently underway.

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

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×