Redox regulation of complement activation in age related macular degeneration.

年龄相关性黄斑变性中补体激活的氧化还原调节。

• 批准号: 20791262
• 负责人: INOMATA Yasuya
• 金额: $ 2.66万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20791262/
• 关键词: 加齢黄斑変性症; 補体; チオレドキシン; LOX-1; レドックス制御; 酸化ストレス

We examined the role of thioredoxin-1 (TRX-1), an endogenous protein with a variety of redox-related roles, in the formation of choroidal neovascularization (CNV). TRX-1-associated proteins from human plasma were isolated by two-dimensional gel electrophoresis with the use of a column coupled with a mutant TRX-1 and were identified by mass spectrometry and proteomics analysis. Complement activation was determined by a fluid-phase. In human plasma, five proteins associated with TRX-1 were identified as apolipoprotein A-I, the CD5 antigen-like member of the scavenger receptor, cysteine-rich superfamily fibrinogen, albumin, and complement factor H (CFH). TRX-1 inhibited the alternative pathway C3 convertase, and its effect was additive with CFH. CNV was induced by laser photocoagulation of the ocular fundus in wild-type and transgenic mice overexpressing human TRX-1 (TRX-1 Tg). Mice were injected intraperitoneally with TRX-1, mutant TRX, or vehicle. The incidence of CNV was evaluated by lectin staining. The incidence of laser-induced CNV was reduced in TRX-1 Tg mice and in C57B/6 mice treated with TRX-1 but not in mutant TRX-1 compared with wild-type mice. Additionally, we elucidated the role of the scavenger receptor, lectin-like oxidized low-density lipoprotein receptor type 1 (LOX-1), in the formation of CNV. In wild-type mice, the relative expression level of LOX-1 mRNA compared with the control increased significantly 6 hours after laser injury and peaked 12 hours after laser injury. At 3 days after laser injury, increases in MCP-1 and VEGF significantly decreased in LOX-1-deficient mice compared with wild-type mice. Morphometric analyses revealed that the induction of CNV formation was significantly inhibited in LOX-1-deficient mice.

我们研究了硫氧还蛋白-1（TRX-1），一种具有多种氧化还原相关作用的内源性蛋白，在形成脉络膜新生血管形成（CNV）中的作用。通过使用与突变体TRX-1结合的色谱柱，通过二维凝胶电泳分离来自人血浆的TRX-1相关蛋白，并通过质谱和蛋白质组学分析鉴定。补体激活由流体相确定。在人血浆中，与TRX-1相关的五种蛋白被鉴定为载脂蛋白A-I，这是清除剂受体的CD5抗原样成员，富含半胱氨酸的超家族纤维蛋白原，白蛋白和补体因子H（CFH）。 TRX-1抑制了替代途径C3转化酶，其效果与CFH相加。通过过表达人TRX-1（TRX-1 Tg）的野生型和转基因小鼠的眼底底眼激光光凝（TRX-1 TG）来诱导CNV。用TRX-1，突变TRX或媒介物腹膜内注射小鼠。通过凝集素染色评估CNV的发生率。与野生型小鼠相比，在TRX-1 TG小鼠中降低了激光诱导的CNV的发生率，在用TRX-1处理的C57B/6小鼠中降低了激光诱导的CNV。此外，我们阐明了清道夫受体，凝集素样氧化的低密度脂蛋白受体1型（LOX-1）在CNV形成中的作用。在野生型小鼠中，LOX-1 mRNA的相对表达水平与对照在激光损伤后6小时显着增加，并在激光损伤后12小时达到峰值。在激光损伤后3天，与野生型小鼠相比，LOX-1缺陷小鼠的MCP-1和VEGF的增加显着降低。形态分析表明，在LOX-1缺陷型小鼠中，CNV形成的诱导显着抑制。

项目成果

Suppression of Choroidal Neovascularization by Thioredoxin-1 via Interaction with Complement Factor H

• DOI: 10.1167/iovs.07-1659
• 发表时间: 2008-11-01
• 期刊: INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
• 影响因子: 4.4
• 作者: Inomata, Yasuya;Tanihara, Hidenobu;Nakamura, Hajime
• 通讯作者: Nakamura, Hajime

Suppression of choroidal neovascularization in lectin-like oxidized low density lipoprotein type-1-deficient mice

凝集素样氧化低密度脂蛋白1型缺陷小鼠脉络膜新生血管的抑制

• 发表时间: 2009
• 期刊: Investigative Ophthalmology and Visual Science 50
• 作者: Inomata Y;Fukushima M;Hara R;Takahashi E;Honjo M;Koga T;Kawaji T;Satoh H;Takeya M;Sawamura T;Tanihara H
• 通讯作者: Tanihara H