Search for a new prevention strategy of proliferative vitreoretinopathy by targeting Smad-dependent epithelial-mesenchymal transition

针对Smad依赖的上皮间质转化寻找增殖性玻璃体视网膜病变的新预防策略

• 批准号: 15591871
• 负责人: SAIKA Shizuya
• 金额: $ 2.11万
• 依托单位: Wakayama Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591871/
• 关键词: Transforming growth factor beta; Proliferative vitreoretinopathy; retinal pigment epithelium; Epithelial-mesenchymal transition; Smad; Signal transduction; Gene therapy; Adenoviral vector; トランスフォーミング成長因子ベータ; 増殖硝子体網膜症; 上皮-間葉系移行; ノックアウトマウス; 細胞培養

Objective: Retinal pigment epithelium is known to undergo epithelial-mesenchymal transition (EMT), which is mediated mainly by transforming growth factor b (TGFb)/Smad2(3)4 signaling. Smad7 suppresses such signaling by blocking this Smad complex from entering the nucleus. Accordingly, we determined the effects of Smad7 gene transfer in prevention of fibrogenic responses by retinal pigment epithelium, one of the major causes of post-retinal detachment proliferative vitreoretinopathy (PVR) in mice.Methods: Retinal detachment induced PVR in a mouse model. An eye received either an adenoviral gene transfer of Smad7 or Cre recombinase gene only. The eyes were histologically analyzed. A retinal pigment epithelial cell line, ARPE-19, was used to determine if Smad7 gene transfection suppresses the fibrogenic response to TGFb2exposure.Results: Smad7 gene transfer inhibited TGFb2/Smad signaling in ARPE 19 cells and expression of collagen type I and TGFb1, but had no effect on their basal levels. In vivo Smad7 overexpression resulted in suppression of Smad2/3 signals and of the fibrogenic response to EMT by retinal pigment epithelium.Conclusion: Smad7 gene transfer suppresses fibrogenic responses to TGFb2 by retinal pigment epithelial cells in vitro and in vivo.Clinical relevance: Smad7 gene transfer might be a new strategy to prevent and treat PVR.

目的：视网膜色素上皮可发生上皮-间质转化（epithelial-mesenchymal transition， EMT）， EMT主要由转化生长因子b (TGFb)/Smad2(3)4信号介导。Smad7通过阻止Smad复合物进入细胞核来抑制这种信号传导。因此，我们确定Smad7基因转移在预防视网膜色素上皮纤维化反应中的作用，视网膜色素上皮纤维化反应是小鼠视网膜脱离后增殖性玻璃体视网膜病变（PVR）的主要原因之一。方法：采用小鼠视网膜脱离诱导PVR模型。眼只接受Smad7或Cre重组酶基因的腺病毒基因转移。对眼睛进行组织学分析。视网膜色素上皮细胞系ARPE-19被用来确定Smad7基因转染是否抑制tgfb2暴露的纤维化反应。结果：Smad7基因的转移抑制了ARPE 19细胞中TGFb2/Smad信号通路以及I型胶原和TGFb1的表达，但对其基础水平无影响。体内Smad7过表达可抑制Smad2/3信号和视网膜色素上皮对EMT的纤维化反应。结论：Smad7基因的转移在体外和体内均可抑制视网膜色素上皮细胞对TGFb2的纤维化反应。临床意义：Smad7基因转移可能是预防和治疗PVR的新策略。

项目成果

of tumor necrosis factor a potentiates transforming growth factor β-mediated pathogenic tissue response during wound healing.

肿瘤坏死因子 a 增强伤口愈合过程中转化生长因子 β 介导的致病组织反应。

• 发表时间: 2006
• 期刊: Am J Pathol 168
• 作者: Saika S;Ikeda K;Yamanaka 0;Flanders KC;Okada Y;Miyamoto T;Kitano A;Ooshima A;Nakajima Y;Ohnishi Y;Kao WW.Loss
• 通讯作者: Kao WW.Loss

Therapeutic effects of adenoviral gene transfer of bone morphogenic protein-7 on a corneal alkali burn model in mice.

腺病毒基因转移骨形态发生蛋白7对小鼠角膜碱烧伤模型的治疗作用。

• 发表时间: 2005
• 期刊: Lab Invest 85
• 作者: Saika S;Ikeda K;Yamanaka O;Flanders KC;Nakajima Y;Miyamoto T;Ohnishi Y;Kao WW-Y;Muragaki Y;Ooshima A.
• 通讯作者: Ooshima A.

Therapeutic effect of topical administration of SN50, an inhibitor of NF-κB, in treatment of corneal alkali burns in mice.

局部给予NF-κB抑制剂SN50对小鼠角膜碱烧伤的治疗效果。

• 发表时间: 2005
• 期刊: Am J Pathol 166
• 作者: Saika S;Miyamoto T;Yamanaka O;Kato T;Ohnishi Y;Flanders KC;Ikeda K;Nakajima Y;Kao WW-Y;Sato M;Muragaki Y;Ooshima A.
• 通讯作者: Ooshima A.

Saika S, et al.: "Sonic hedgehog. Its expression and role in healing corneal epithelium"Invest.Ophthalmol.Vis.Sci.. 45(in press). (2004)

Saika S 等人：“Sonic hedgehog。其在角膜上皮愈合中的表达和作用”Invest.Ophthalmol.Vis.Sci.. 45（印刷中）。

Adenoviral gene transfer of BMP-7, ld2 or ld3 suppresses injury-induced epithelial-mesenchymal transition of lens epithelium in mice.

BMP-7、ld2 或 ld3 的腺病毒基因转移抑制小鼠中损伤诱导的晶状体上皮的上皮-间质转化。

• 发表时间: 2006
• 期刊: Am J Physiol- Cell Physiol- 290
• 作者: Saika S;Ikeda K;Yamanaka O;Flanders KC;Ohnishi Y;Nakajima Y;Muragaki Y;Ooshima A
• 通讯作者: Ooshima A