Abstract
Purpose :
Preclinical evidence supports the efficacy of epigenetic, conditioning-based therapeutics for acute and chronic retinal disease. Changes in gene expression triggered by conditioning stimuli typically results in robust levels of injury resilience. Our lab has an established history of using repetitive hypoxic conditioning (RHC) as an epigenetic stimulus in mice to afford long-lasting protection against glaucomatous degeneration of RGC soma and axons. Last year, we showed that treating male and female Swiss-Webster ND4 mice for 4 months with RHC, prior to mating, resulted in robust functional protection (scotopic ERG) against retinal ischemia in their (untreated) F1 offspring. However, the molecular phenotype underlying this inherited neuroprotective state is unknown.
Methods :
To this end, we performed quantitative mass spectroscopy on the nonischemic and (7-day) post-ischemic retinae from adult F1 mice derived from RHC-treated F0 parents (F0-RHC) and the nonischemic and postischemic retinae from matched F1 mice derived from untreated F0 control parents (F0-CTL). We report herein proteins that exhibited at least a significant, 1.5-fold change in abundance between groups, using a <1% FDR.
Results :
(see table) Nonischemic retinae from F1 mice born to F0-RHC parents exhibited 364 upregulated and 110 downregulated proteins relative to nonischemic retinae of F1 mice born to F0-CTL parents, reflecting the inter-generational reach of the RHC-induced epigenetic response. Ischemic F1 retinae from F0-RHC parents exhibited 135 upregulated proteins and 124 downregulated proteins relative to their fellow nonischemic retinae, and 73 upregulated proteins and 198 downregulated proteins relative to ischemic F1 retinae of F0-CTL parents. Of note, 42 of the upregulated and 63 of the downregulated proteins were identical in these latter groups.
Conclusions :
Thus, F1 mice derived from RHC-treated parents exhibit a uniquely remodeled retinal proteome prior to, as well as after, ischemia. Bioinformatic analyses yielded a broad and deep list of pathways and networks significantly enriched in these differentially expressed proteins. Defining the injury-resilient retinal proteome in F0 mice directly treated with RHC, and that of F1 animals that inherit resilience from their RHC-treated F0 parents, will facilitate the development of therapeutics for ischemic retinopathies.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.