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Proteomic Landscape of the Human Choroid-Retinal Pigment Epithelial Complex.
JAMA Ophthalmol. 2014 Jul 24;
Authors: Skeie JM, Mahajan VB
Importance: Differences in geographical protein expression in the human choroid-retinal pigment epithelial (RPE) complex may explain molecular predisposition of regions to ophthalmic diseases such as age-related macular degeneration.
Objective: To characterize the proteome of the human choroid-RPE complex and to identify differentially expressed proteins in specific anatomic regions.
Design, Setting, and Participants: Experimental study of choroid-RPE tissue from 3 nondiseased eyes. The choroid-RPE complex underwent biopsy from beneath the foveal, macular, and peripheral retina. Protein fractions were isolated and subjected to multidimensional liquid chromatography and tandem mass spectrometry. A bioinformatic pipeline matched peptide spectra to the human proteome, assigned gene ontology classification, and identified protein signaling pathways unique to each of the choroid-RPE regions.
Main Outcomes and Measures: Mean number of mass spectra, statistically significant differentially expressed proteins, gene ontology classification, and pathway representation.
Results: We identified a mean of 4403 unique proteins in each of the foveal, macular, and peripheral choroid-RPE tissues. Six hundred seventy-one differentially expressed proteins included previously known risk factors for retinal diseases related to oxidative stress, inflammation, and the complement cascade. Gene ontology analysis showed that unique categories in the foveal and macular regions included immune process proteins as well as protein complexes and plasma membrane proteins. The peripheral region contained unique antioxidant activity proteins. Many proteins had the highest expression in the foveal or macular regions, including inflammation-related proteins HLA-A, HLA-B, and HLA-C antigens; intercellular adhesion molecule 1 (ICAM-1); S100; transcription factor ERG; antioxidant superoxide dismutase 1 (SOD1); chloride intracellular channel 6 ion (CLIC6); activators of the complement cascade C1q, C6, and C8; and complement factor H. Proteins with higher expression in the periphery included bestrophin 1 (BEST1), transcription factor RNA binding motif protein 39 (RBM39), inflammatory mediator macrophage migration inhibitory factor, antioxidant SOD3, ion channel voltage-dependent anion-selective channel protein 3 (VDAC3), and complement inhibitor CD55. The complement activation was among the highest represented pathways (P < 7.5e-13).
Conclusions and Relevance: This proteomic data set identifies novel molecular signatures in anatomically sensitive regions of the choroid-RPE complex. The findings give mechanistic insight into choroid-RPE function, reveal important choroid-RPE processes, and prioritize new pathways for therapeutic targeting.
PMID: 25058583 [PubMed - as supplied by publisher]
Is age-related macular degeneration a microvascular disease?
Adv Exp Med Biol. 2014;801:283-9
Authors: Mullins RF, Khanna A, Schoo DP, Tucker BA, Sohn EH, Drack AV, Stone EM
Age-related macular degeneration (AMD) is a common, degenerative disease of the central retina affecting millions of elderly in the USA alone and many more worldwide. A better understanding of the pathophysiology of AMD will be essential for developing new treatments. In this review, we discuss the potential impact of complement complex deposition at the choriocapillaris of aging eyes and the relationship between choriocapillaris loss and drusen formation. We further propose a model that integrates genetic and anatomical findings in AMD and suggest the implications of these findings for future therapies.
PMID: 24664709 [PubMed - indexed for MEDLINE]