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Proteomic analysis of the human retina reveals region-specific susceptibilities to metabolic- and oxidative stress-related diseases

机译:对人类视网膜的蛋白质组学分析揭示了特定区域对代谢和氧化应激相关疾病的敏感性

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摘要

Differences in regional protein expression within the human retina may explain molecular predisposition of specific regions to ophthalmic diseases like age-related macular degeneration, cystoid macular edema, retinitis pigmentosa, and diabetic retinopathy. To quantify protein levels in the human retina and identify patterns of differentially-expressed proteins, we collected foveomacular, juxta-macular, and peripheral retina punch biopsies from healthy donor eyes and analyzed protein content by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein expression was analyzed with 1-way ANOVA, gene ontology, pathway representation, and network analysis. We identified a mean of 1,974 proteins in the foveomacular retina, 1,999 in the juxta-macular retina, and 1,779 in the peripheral retina. Six hundred ninety-seven differentially-expressed proteins included those unique to and abundant in each anatomic region. Proteins with higher expression in each region include: heat-shock protein 90-alpha (HSP90AA1), and pyruvate kinase (PKM) in the foveomacular retina; vimentin (VIM) and fructose-bisphosphate aldolase C (ALDOC); and guanine nucleotide-binding protein subunit beta-1 (GNB1) and guanine nucleotide-binding protein subunit alpha-1 (GNAT1) in the peripheral retina. Pathway analysis identified downstream mediators of the integrin signaling pathway to be highly represented in the foveomacular region (P = 6.48 e–06). Metabolic pathways were differentially expressed among all retinal regions. Gene ontology analysis showed that proteins related to antioxidant activity were higher in the juxta-macular and the peripheral retina, but present in lower amounts in the foveomacular retina. Our proteomic analysis suggests that certain retinal regions are susceptible to different forms of metabolic and oxidative stress. The findings give mechanistic insight into retina function, reveal important molecular processes, and prioritize new pathways for therapeutic targeting.
机译:人类视网膜内区域蛋白表达的差异可能解释了眼科疾病(如年龄相关性黄斑变性,黄斑囊样水肿,色素性视网膜炎和糖尿病性视网膜病变)的特定区域的分子易感性。为了量化人类视网膜中的蛋白质水平并鉴定差异表达的蛋白质的模式,我们从健康的供体眼睛收集了黄斑,近端黄斑和周边视网膜穿孔活检,并通过液相色谱-串联质谱(LC-MS /多发性硬化症)。用1向ANOVA,基因本体论,途径表示和网络分析来分析蛋白质表达。我们确定了黄斑前视网膜平均1,974个蛋白,近黄斑视网膜1,999个蛋白和外周视网膜1,779个蛋白。 967个差异表达的蛋白质包括每个解剖区域中独特且丰富的蛋白质。在每个区域中表达较高的蛋白质包括:黄膜视网膜中的热休克蛋白90-alpha(HSP90AA1)和丙酮酸激酶(PKM);以及波形蛋白(VIM)和果糖二磷酸醛缩酶C(ALDOC);鸟嘌呤核苷酸结合蛋白亚基β-1(GNB1)和鸟嘌呤核苷酸结合蛋白亚基α-1(GNAT1)。途径分析确定整合素信号传导途径的下游介质在黄斑区中高度代表(P = 6.48 e-06)。代谢途径在所有视网膜区域之间差异表达。基因本体分析表明,与抗氧化活性有关的蛋白质在近黄斑和周围视网膜中较高,但在黄膜视网膜中含量较低。我们的蛋白质组学分析表明,某些视网膜区域易受不同形式的代谢和氧化应激的影响。这些发现提供了对视网膜功能的机械洞察力,揭示了重要的分子过程,并为治疗靶向确定了新的途径。

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