The role of advanced glycaiton end products (AGEs) in the pathogenesis of age related macular degeneration and the development of a new modality of therapy

晚期糖基化终产物（AGE）在年龄相关性黄斑变性发病机制中的作用和新治疗方式的开发

• 批准号: 12671711
• 负责人: MURATA Toshinori
• 金额: $ 2.5万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671711/
• 关键词: advaenced glycation end products; monocyte chemoattractant protein-1; angeiogenesis; macrohpages; age related macular degeneration; In situ hybridization; 加齢黄班変性; AGEs; 網膜色素上皮細胞

The aim of the present study was to elucidate the mechanisms how the advanced glycation end products (AGEs) that deposited in soft drusen induce macrophage infiltration. We hypothesized that these macrophages induce choroidal neovasclarization. The following results were obtained in this study.1) AGEs induce an overexpression of monocyte chemoattractant protein-1 (MCP-1) in the cultured retinal pigment epithelial (RPE) cells.An overexpression of MCP-1 when stimulated by AGEs was detected by ELISA. In the surgical specimens, the RPE cells that had phagocytosed AGEs were positive for MCP-1 by immunohistochemistry. The adjacent macrophages were positive for tumor necrosis factor-1 (TNF- 1) and Inteleukin-1β (IL-1β). These cytokines then induced over-expression of vascular endothelial growth factor (VEGF) that has been reported to be the key angiogenic factor for choroidal neovasclarization.2) Sub-RPE cells deposition of AGEs induce macrophage infiltration into this space.AGEs were injected into the sub-retinal space of the rat eyes, which Induced a prominent macrophage Infiltration.

本研究的目的是阐明沉积在软膜中的晚期糖基化终产物（AGEs）诱导巨噬细胞浸润的机制。我们假设这些巨噬细胞诱导脉络膜新生血管的形成。本研究得到以下结果：1) AGEs诱导培养的视网膜色素上皮（RPE）细胞中单核细胞趋化蛋白-1 （MCP-1）过表达。ELISA检测了MCP-1在AGEs刺激下的过表达。在手术标本中，吞噬AGEs的RPE细胞免疫组化检测MCP-1阳性。邻近巨噬细胞肿瘤坏死因子-1 （TNF- 1）和白细胞介素-1β (IL-1β)阳性。这些细胞因子随后诱导血管内皮生长因子（VEGF）的过度表达，据报道，VEGF是脉络膜新生血管形成的关键血管生成因子。2) AGEs的亚rpe细胞沉积诱导巨噬细胞向该间隙浸润。将AGEs注入大鼠视网膜下间隙，可诱导巨噬细胞明显浸润。

项目成果

Murata T, Cui J, Taba KE, Oh JY, Spee C, Hinton DR, Ryan SJ.: "The possibility of gene therapy for the treatment of choroidal neovascularization"Ophthalmology. 107(7). 1364-73 (2000)

Murata T、Cui J、Taba KE、Oh JY、Spee C、Hinton DR、Ryan SJ.：“基因疗法治疗脉络膜新生血管的可能性”眼科。

Hangai M, Murata T, Miyawaki N, Spee C, LimJI, He S, Hinton DR, Ryan SJ.: "Angiopoietin-1 upregulation by vascular endothelial growth factor in human retinal pigment epithelial cells"Invest Ophthalmol Vis Sci. 42(7). 1617-25 (2001)

Hangai M、Murata T、Miyawaki N、Spee C、LimJI、He S、Hinton DR、Ryan SJ.：“人视网膜色素上皮细胞中血管内皮生长因子对血管生成素-1 的上调”Invest Ophasemol Vis Sci。

Joussen AM, Murata T, Tsujikawa A, Bursell SE, Adamis AP. Kirchhof B: "Leukocyte-mediated endothelial cell injury and death in the diabetic retina"Am J Pathol. 158(1). 147-52 (2001)

Joussen AM、Murata T、Tsujikawa A、Bursell SE、Adamis AP。

Joussen AM, Murata T et al.: "Leukocyte-mediated endothelial cell injury and death in the diabetic retina"Am J Pathol. 158・1. 147-152 (2001)

Joussen AM、Murata T 等：“糖尿病视网膜中白细胞介导的内皮细胞损伤和死亡”Am J Pathol 158・1（2001）。

Murata T et al.: "Peroxisome proliferator-activated receptor-gamma ligands inhibit choroidal neovascularization"Invest Ophthalmol Vis Sci. 41・8. 2309-2317 (2000)

Murata T 等：“过氧化物酶体增殖物激活受体-γ 配体抑制脉络膜新生血管” Invest Ophasemol Vis Sci 41・8（2000）。