Analyse the mechanism of choroidal neovascularization (CNV) induced by oxidized LDL receptor and develope the therapy against CNV

分析氧化LDL受体诱导脉络膜新生血管（CNV）的机制并开发针对CNV的治疗方法

• 批准号: 17591842
• 负责人: TSUTSUI Junichiro
• 金额: $ 2.3万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591842/
• 关键词: scavenger receptor; LOX-1; choroidal neovascularization; Age-related macular degeneration; statin; 脈絡膜新生血管

1. Macrophage cells accumulated in choroidal neovascular membranes excised surgically during submacular operation. A portion of them was positively immunostained with antibodies against Class-A scavenger receptors (SR-A) that were important for aterosclerosis. Neovascular membranes other than Age-related macular degeneration also contained SR-A positive macrophage cells. It is possibile that scavenger receptors have an important role for the choroidal neovascularization.2. The experimental models of laser-induced choroidal neovascularization (CNV) were prepared in wild type and LOX-1 gene knockout (LOX-1 KO) mice. The expression of LOX-1 mRNA was induced after exposure. The protein level of precursor matrix metalloproteinases (MMPs) was increased and MMPs were activated in wild mice, but in LOX-1 KO mice, the expression of precursor MMPs and activation of MMPs were suppressed. In wild type mice neovascularity within the laser-exposed area was detected with 93 %, but in LOX-1 KO mice it … More was reduced with 43 %. These data suggest that LOX-1 may promote the choroidal neovascularization.3. To evaluate the effect of the administration of the 3-hydroxy-3-methylglutaryl co-enzyme A(HMG-CoA) reductase inhibitors (pitavastatin) on CNV, that was known to suppress hyperlipidemia and plaque formation in atherosclerosis, the experimental models of laser-induced CNV was created in rats. Pitavastatin-treated rats had significantly less fluorescence leakage in laser-exposed area. Both the area and the thickness of CNV in pitavastatin-treated rais were significantly reduced compared with control. These indicate that the therapeutic dose of pitavastatin effectively suppressed experimental CNV in rats.4. In order to screen the protein cotained in the human intraocular fluid, the proteomics analysis was applied to get the two-dimensional electrophoresis profile; from the aqueous humors excised surgically during cataract operations. The silver-staining protein spots were picked up and identified by matrix-a: sisted laser desorption/ionization time-of-flight mass spectrometry and data base searching. Alubmin, alloalubmin, transferrin, apolipoprotein, vitamin D binding protein, transthretin, and antitrypsin were major proteins in the human aqueous humors Less

1.黄斑下手术切除的脉络膜新生血管膜中聚集巨噬细胞。其中一部分的 A 类清道夫受体 (SR-A) 抗体呈阳性免疫染色，这对动脉粥样硬化很重要。除年龄相关性黄斑变性外，新生血管膜也含有 SR-A 阳性巨噬细胞。清道夫受体可能在脉络膜新生血管形成中起重要作用。 2．在野生型和LOX-1基因敲除（LOX-1 KO）小鼠中制备激光诱导脉络膜新生血管（CNV）实验模型。 LOX-1 mRNA 的表达在暴露后被诱导。在野生小鼠中，前体基质金属蛋白酶（MMP）的蛋白水平增加并且MMP被激活，但在LOX-1 KO小鼠中，前体MMP的表达和MMP的激活被抑制。在野生型小鼠中，激光照射区域内的新生血管检测率为 93%，但在 LOX-1 KO 小鼠中，新生血管减少了 43%。这些数据表明LOX-1可能促进脉络膜新生血管形成。3．众所周知，3-羟基-3-甲基戊二酰辅酶 A (HMG-CoA) 还原酶抑制剂（匹伐他汀）可抑制动脉粥样硬化中的高脂血症和斑块形成，为了评估给予 CNV 的效果，在大鼠中创建了激光诱导 CNV 的实验模型。匹伐他汀治疗的大鼠激光暴露区域的荧光泄漏明显减少。与对照相比，匹伐他汀治疗组的 CNV 面积和厚度均显着减少。表明治疗剂量的匹伐他汀能有效抑制大鼠实验性CNV。 4．为了筛选人眼内液中所含的蛋白质，应用蛋白质组学分析获得二维电泳图谱；来自白内障手术期间手术切除的房水。通过矩阵-a：辅助激光解吸/电离飞行时间质谱和数据库搜索拾取并鉴定银染蛋白点。白蛋白、同种白蛋白、转铁蛋白、载脂蛋白、维生素 D 结合蛋白、转苏蛋白和抗胰蛋白酶是人房水中的主要蛋白质。

项目成果

Rho-associated protein kinase inhibitor, Y-27632, induces alterations in adhesion, contraction and motility in cultured human trabecular meshwork cell.

Rho 相关蛋白激酶抑制剂 Y-27632 可诱导培养的人小梁网细胞粘附、收缩和运动的改变。

• 发表时间: 2006
• 期刊: Experimental Eye Research 82
• 作者: Koga T;Koga T;Awai M;Tsutsui J;Yue BYJT;Tanihara H.
• 通讯作者: Tanihara H.

Effect of pitavastatin on experimental choroidal neovascularization in rats.

• DOI: 10.1016/j.exer.2007.02.005
• 发表时间: 2007-06
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: N. Sagara;T. Kawaji;A. Takano;Yasuya Inomata;M. Inatani;M. Fukushima;H. Tanihara

Rho-associated protein kinase inhibitor, Y-27632, induces alterations in adhesion, contraction and motility in cultured human trabecular meshwork cell

Rho 相关蛋白激酶抑制剂 Y-27632 可诱导培养的人小梁网细胞粘附、收缩和运动的改变

• 发表时间: 2006
• 期刊: Experimental Eye Research 82
• 作者: Koga T;Koga T;Awai M;Tsutsui J;Yue BYJT;Tanihara H
• 通讯作者: Tanihara H

Effect of pitavastatin on experimental choroidal neovascularization in rat

匹伐他汀对大鼠实验性脉络膜新生血管的影响

• 期刊: Experimental Eye Research (In press)
• 作者: Sagara N;Kawaji T;Takano A;Inomata Y;Inatani M;Fukushima M;Tanihara H
• 通讯作者: Tanihara H