March 2012
Volume 53, Issue 14
ARVO Annual Meeting Abstract  |   March 2012
Genetically-related Inflammatory Priming and Failing Retinal Maintenance Predispose to Age-Related Retinal Degeneration in Mice
Author Affiliations & Notes
  • Debarshi Mustafi
    Case Western Reserve University, Cleveland, Ohio
  • Hideo Kohno
    Case Western Reserve University, Cleveland, Ohio
  • Krzysztof Palczewski
    Case Western Reserve University, Cleveland, Ohio
  • Tadao Maeda
    Ophthal & Visual Sciences,
    Case Western Reserve University, Cleveland, Ohio
  • Footnotes
    Commercial Relationships  Debarshi Mustafi, None; Hideo Kohno, None; Krzysztof Palczewski, None; Tadao Maeda, None
  • Footnotes
    Support  NIH Grants EY019478 and K08EY019880
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 6510. doi:
  • Views
  • Share
  • Tools
    • Alerts
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Debarshi Mustafi, Hideo Kohno, Krzysztof Palczewski, Tadao Maeda; Genetically-related Inflammatory Priming and Failing Retinal Maintenance Predispose to Age-Related Retinal Degeneration in Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6510.

      Download citation file:

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

  • Supplements

Purpose: : Understanding of the pathogenesis of age-related retinal degeneration (ARD) is complicated by the multi-factorial nature of the disease. By studying a model mouse that exhibits ARD starting at a young age before disease onset, we sought to identify genetic factors that predispose and lead to the progression of disease.

Methods: : The inbred A/J mouse develops ARD much more rapidly than mice of other genetic backgrounds. The age-related increase in retinal pathology was characterized by in vivo as well as high resolution ex vivo imaging modalities. The decline in visual function was assessed by retinoid and electroretinogram measurements. RNA-Sequencing (RNA-Seq) of young eye tissues before ARD signs in model mice provided full coverage of transcriptomes. The differential gene expression profile was characterized using Ingenuity Pathway Analysis (IPA) to identify abnormally functioning genetic networks that predispose A/J mice to ARD. The expression level changes were validated by RT-PCR and immunoblotting and localized in the retina with immunohistochemistry.

Results: : A/J mice exhibited pronounced age-related retinal degeneration at 8 months of age and the degeneration was accompanied by inflammatory changes in the retina. RNA-Seq of eye tissue from young A/J identified 322 differentially expressed genes that were statistically significantly when compared to controls. IPA analysis of these revealed an activated inflammatory network in A/J mice characterized by inflammatory priming as well as defective cellular stress response and maintenance of normal photoreceptor pathways in A/J mice. Localization of differentially expressed targets identified the RPE as the primary ARD-targeted site.

Conclusions: : RNA-Seq of ARD model mice revealed key genetic aberrations that arise before phenotypic onset of symptoms, providing a new paradigm to help understand the genetic components involved in the pathogenesis of ARD. The combination of subtle genetic differences that exist in the A/J eye predispose it to an immune mediated pathology, which transitions to a chronic state with increasing age, emanating from dysfunctional RPE cells. Moreover, decline in enzymes that normally protect against oxidative damage with age influence expression and function of critical inflammatory regulatory factors that further initiate the progression of age-related decline.

Keywords: retinal degenerations: cell biology • retina • retinal pigment epithelium 

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.