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Investigation of the mechanism of diabetic macular edema

糖尿病性黄斑水肿发生机制的探讨

基本信息

批准号：
15591861
负责人：
HATA Yasuaki
金额：
$ 2.18万
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：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591861/
关键词：
VEGF KDR PPARgamma Sp1 Hyalocyte PDGF TGF-beta Rho-kinase VEGF VPF Fibrinogen HIF-1 SU5416

项目摘要

The main causes of visual disturbance due to diabetic retinppathy are macular edema based on vascular hyperpermeability and proliferative tissue based on the neovascularization. Vascular endothelial growth factor (VEGF=vascular permeability factor;VPF) is known to be closely associated with the pathogenesis of diabetic retinopathy.We previously reported that the effect of VEGF was not only due to the amount of VEGF itself but also due to the amount of the expression of its receptor (KDR) on the surface of retinal capillary endothelial cells. Additionally, we reported that the expression of KDR gene is positively regulated by the transcription factor Sp1.In this study, we clarified that PPARgamma agonist, which is already in clinical use as to normalize the insulin resistant state, could down-regulate the expression of KDR gene through the inhibition of the binding of Sp1 to the KDR promoter region. These result indicate that the PPARgamma agonist might be a hopeful drug for the treatme … More nt of diabetic retinopathy through not only normalizdng the insulin-resistent state but also down-regulating the expression of VEGF receptor on the retinal capillary endothelial cells.In addition, while the mechanisms are still unclear, fractional force of the vitreous to the macular area is thought to be one of the pathogenesis of diabetic macular edema. We isolated hyalocytes, which are thought to be rnacrophage lineage, from the vitreous and examined its functional properties under various circumstances. Platelate-derived growth factor-BB(PDGF-BB), which is known to be up-regulated in the diabetic eyes, enhanced the proliferation, chamotaxis and gel contraction by the hyalocytes. Furthermore, TGF-beta, whose activity is also known to be up-regulated in the diabetic eyes, strongly promoted tonic and continuous gel contraction as compared with PDGF.We further demonstrated that the gel contraction mechanism due to PDGF-BB and TGF-beta is mainly mediated through rho-kinase activity. We thus demonstrated that the rho-kinase inhibitor (Hydroxyfasudil), alredy in clinical use for cerebellar vascular spasm could inhibit the gel contraction by the hyalocyte. We thus indicated the possibility of new strategy for the treatment of diabetic retinopathy. Less

糖尿病视网膜病变导致视力障碍的主要原因是基于血管渗透性过高的黄斑水肿和基于新血管形成的增生组织。血管内皮生长因子（Vascular endothelial growth factor，VEGF）与糖尿病视网膜病变的发生密切相关，我们曾报道VEGF的作用不仅与VEGF本身的量有关，还与视网膜毛细血管内皮细胞表面VEGF受体（KDR）的表达量有关。此外，我们还发现KDR基因的表达受转录因子Sp1的正调控。本研究阐明了已在临床上用于改善胰岛素抵抗状态的PPARgamma激动剂可通过抑制Sp1与KDR启动子区的结合来下调KDR基因的表达。这些结果表明，PPARgamma激动剂可能是一种有希望的治疗药物。 ...更多信息糖尿病视网膜病变的发病机制不仅与胰岛素抵抗状态的正常化有关，还与视网膜毛细血管内皮细胞VEGF受体表达的下调有关，此外，玻璃体对黄斑区的摩擦力被认为是糖尿病黄斑水肿的发病机制之一，但其机制尚不清楚。我们从玻璃体中分离出被认为是巨噬细胞谱系的透明细胞，并在各种情况下检查其功能特性。血小板源性生长因子-BB（PDGF-BB），这是已知的上调，在糖尿病的眼睛，增强了透明细胞的增殖，趋化性和凝胶收缩。此外，TGF-β，其活性也被称为在糖尿病眼睛上调，强烈促进强直和连续的凝胶收缩相比PDGF.We进一步证明，由于PDGF-BB和TGF-β的凝胶收缩机制主要是通过rho激酶活性介导的。因此，我们证明，rho激酶抑制剂（羟法舒地尔），已经在临床上用于小脑血管痉挛，可以抑制透明细胞的凝胶收缩。提示糖尿病视网膜病变治疗新策略的可能性。少

项目成果

期刊论文数量（50）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fibrinogen stimulates in vitro angiogenesis by choroidal endothelial cells via autocrine VEGF

DOI：
10.1007/s00417-004-0910-2
发表时间：
2004-04
期刊：
Graefe's Archive for Clinical and Experimental Ophthalmology
影响因子：
0
作者：
S. Shiose;Y. Hata;Y. Noda;Y. Sassa;A. Takeda;H. Yoshikawa;K. Fujisawa;T. Kubota;T. Ishibashi
通讯作者：
S. Shiose;Y. Hata;Y. Noda;Y. Sassa;A. Takeda;H. Yoshikawa;K. Fujisawa;T. Kubota;T. Ishibashi

Bifunctional properties of PPARg1 in KDR gene regulation mediated via interaction with both Sp1 and Sp3.

PPARg1 在 KDR 基因调控中的双功能特性通过与 Sp1 和 Sp3 的相互作用介导。