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W. D. Ferrell, F. R. Vazquez-Chona, B. W. Jones, R. E. Marc; Metabolic Biomarkers of Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5202.
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The goals of this study are to relate the classic sequelae of photoreceptor degeneration to small molecular metabolic signals and define metabolic states that define survival or apoptotic pathways in photoreceptors.
The light-induced retinal damage (LIRD) model in albino mice has been used for decades of biochemical, genetic, molecular and pharmacological investigations and ensures an adult onset, coherent timing of photoreceptor stress, built in controls in dorsal retina and extreme retinal remodeling similar to remodeling induced by age-related macular degeneration. Comparing metabolic states with specific cellular transformations is possible through the integration of high resolution, N-dimensional metabolic profiling (Computational Molecular Phenotyping, CMP) with electron microscopy, classic photoreceptor proteome profiling, as well as assays for mitochondrial function, proliferation, and cell death.
We found classic features of photoreceptor degeneration including rhodopsin mislocalization, membrane blebbing, and nuclear fragmentation correlated with specific metabolic profiles. An early metabolic anomaly was the redistribution of mitochondrial metabolites to the cytoplasm: mainly glutamate and aspartate. Late stage apoptotic events of nuclear fragmentation correlate with depletion of glutamate and aspartate in photoreceptors.
Current research aims to discover how changes in glutamate and aspartate distribution contribute to mitochondrial dysfunction and energy depravation. CMP is an ideal platform to integrate various levels of cell regulation (metabolism, energetics and proteomics) with high spatial resolution and quantitative analyses. Thus, CMP is paving the way toward a unified explanation of how oxidative stress imposes degeneration and ultimately cell death in photoreceptors.
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