The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration.
The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration.
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DOI：
10.1371/journal.pone.0002339
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发表时间：
2008-06-04
期刊：
影响因子：
3.7
通讯作者：
Neufeld AH
中科院分区：
文献类型：
--
作者：
Chen H;Liu B;Lukas TJ;Neufeld AH
虽然年龄是老年性黄斑变性（AMD）的最大危险因素的说法被广泛接受，但对该临床声明的细胞和分子解释并不普遍。AMD研究的主要焦点是视网膜色素上皮（RPE）/脉络膜。本研究的目的是描述RPE/脉络膜随年龄的变化，这可能为AMD的发展提供背景。我们比较了年轻和老年小鼠RPE/脉络膜的转录谱、关键蛋白水平和组织学。使用三种统计方法，微阵列数据显示老年小鼠的显著变化。有315个基因的差异表达与年龄，这些基因中的大多数与免疫反应和炎症活动。在老年RPE/脉络膜中具有显著数量的上调基因的典型途径包括白细胞外渗、补体级联、自然杀伤细胞信号传导和IL-10信号传导。相比之下，相邻的神经视网膜表现出完全不同的年龄相关变化。参与白细胞外渗和补体途径的蛋白质水平在正常的老年RPE/脉络膜中持续增加。此外，在老化的RPE/脉络膜中，白细胞吸引信号、趋化因子配体2（Ccl 2）的基因表达和蛋白水平增加。在老年动物中，脉络膜循环中的白细胞明显外渗和积聚到布鲁赫膜上并进入RPE。这些表型变化表明正常老年小鼠的RPE/脉络膜已成为免疫活性组织。存在来自正常、老化的RPE/脉络膜的信号，其从循环中募集白细胞并激活补体级联。随着年龄的增长，在RPE/脉络膜中发生的这些年龄相关的变化，就它们在人视网膜中发生的程度而言，可能为免疫活性调节错误提供背景，从而导致老年个体中出现AMD。
Although the statement that age is the greatest risk factor for Age-related macular degeneration (AMD) is widely accepted, the cellular and molecular explanations for that clinical statement are not generally known. A major focus of AMD research is the retinal pigment epithelium (RPE)/choroid. The purpose of this study was to characterize the changes in the RPE/choroid with age that may provide a background for the development of AMD. We compared the transcriptional profiles, key protein levels and histology of the RPE/choroid from young and old mice. Using three statistical methods, microarray data demonstrated marked changes in the old mouse. There were 315 genes differentially expressed with age; most of these genes were related to immune responses and inflammatory activity. Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling. By contrast, the adjacent neural retina showed completely different age-related changes. The levels of proteins that participate in leukocyte extravasation and complement pathways were consistently increased in the normal, aged RPE/choroid. Furthermore, there was increased gene expression and protein levels of leukocyte attracting signal, chemokine ligand 2 (Ccl2) in aged RPE/choroid. In old animals, there was marked extravasation and accumulation of leukocytes from the choroidal circulation onto Bruch's membrane and into the RPE. These phenotypic changes indicate that the RPE/choroid in the normal, old mouse has become an immunologically active tissue. There are signals from the normal, aged RPE/choroid which recruit leukocytes from the circulation and activate the complement cascade. These age-related changes that occur in the RPE/choroid with age, to the extent that they occur in the human retina, may provide the background for an error in regulation of immunological activity to cause AMD to appear in an elderly individual.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
影响因子：
15.8
作者：
Apte, Rajendra S.;Richter, Jennifer;Herndon, John;Ferguson, Thomas A.
通讯作者：
Ferguson, Thomas A.
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
5.4
作者：
Frick, C;Odermatt, A;Parkos, CA
通讯作者：
Parkos, CA