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G. Tezel, X. Yang, C. Luo, J. Cai, W. M. Pierce, M. H. Kuehn; Proteomic Analysis of Human Retina: Ocular Hypertension versus Glaucoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2186.
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As part of ongoing proteomic studies to elucidate pathogenic mechanisms of glaucomatous neurodegeneration, this study focused on alterations in retinal protein expression in ocular hypertensive donors in comparison to glaucomatous donors and normotensive controls.
Human retinal protein samples were obtained from donors with ocular hypertension (with no clinically detectable neuronal damage or visual field defect; n:2) or glaucoma (n:10) as well as normotensive controls (n:10).Tryptic peptides of protein mixtures were analyzed by LC-MS/MS using both a label-free approach and oxygen isotope labeling for relative quantification of protein expression. Bioinformatic analysis of the MS/MS data utilized the Ingenuity Pathways Analysis.
Proteomic analysis detected expression and differential regulation of hundreds of proteins with high confidence. The identified proteins included those with predicted protein locations within different cellular compartments, including nucleus, mitochondria, endoplasmic reticulum, cytoskeleton, and cell membrane. Comparison of the MS/MS data supported that many of the proteins exhibiting an over two-fold differential regulation in ocular hypertensive samples represented an intrinsic stress/defense response similar to that detected in glaucoma, although glaucomatous samples also exhibited an ongoing cell death process. Differentially regulated proteins in ocular hypertensive samples included cytoskeletal and cellular transport proteins, mitochondrial enzymes, synaptic and neurite outgrowth proteins, matrix remodeling, cell adhesion and cell-cell interaction proteins, MAPK, G-protein and calcium signaling molecules, glutamate transporters, ion channels, nerve growth factor receptors, heat shock proteins, 14-3-3 proteins, anti-oxidants, iron regulators, and DNA repair enzymes. Bioinformatic analysis established extended functional networks of related signaling pathways.
Findings of this comparative proteomic study for the first time provide comprehensive information about the cellular response in ocular hypertensive human retinas at the protein level. This information helps improve the understanding of ocular hypertension-related early alterations in the human retina as opposed to alterations detected in eyes with clinically manifest glaucomatous damage, and supports that a "threshold" of proteomic alterations determines the initiation of neurodegenerative injury in glaucoma following an initial period of defense response exhibiting individual differences.
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