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Study on the mechanism of vascular injury by novel species of advanced glycation endoproducts

新型晚期糖基化内产物损伤血管机制研究

基本信息

批准号：
14580645
负责人：
WATANABE Takuo
金额：
$ 2.56万
依托单位：
KANAZAWA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580645/
关键词：
advanced glycation endproducts AGE RAGE diabetic angiopath MAP kinase VCAM-1 esRAGE life-style related diseases RAGE knockout

项目摘要

In this research, we revealed that the novel species of advance glycation endproducts (AGE), whose level in serum is elevated in diabetic patients, do bind to their cellular receptor RAGE and induce intracellular signals.We also identified a novel splicing variant of RAGE-endogenous secretory RAGE (esRAGE)-and found that this variant has protective effect against vascular injury induced by the novel AGE species. Moreover, we found the significant coirelation between serwn esRAGE level and susceptibility of some life-style related diseases.(1) We demonstrated that the novel AGE species, which is generated by incubating bovine serum albumin with glyceraldehyde or glycolaldehyde, strongly binds to cellular RAGE at comparable dissociation constants calculated by the suiface plasmon resonance method.(2) We mapped the binding region of the novel AGEs on RAGE at an inununoglobulin V-domain-like region on its N-terminal end.(3) We demonstrated that the interaction of the new AGEs to RAGE activated MAP kinase signaling pathway and induced V CAM-i expression in cultured human endothelialcells.(4) We created RAGE knockout mice and demonstrated that the development of diabetic nephropa thy was dramatically suppressed in the absence of RAGE..(5) We isolated a novel splicing variant of RAGE from human endothelial cells that lacks transmembrane domain and is secreted from cells, and termed this novel variant esRAGE (~ndogenous secretory RAGE).(6) Furthennore we found that esRAGE has a protective effect against the vascular injuly induced by the novel AGEs, by extracellular capture of the RAGE lingads.(7) We established esRAGE ELISA system and analyzed serum level of esRAGE in patients with life-style related deseases. Then we found significant correlation between serum esRAGE level and susceptibility of some life-style related diseases, suggesting that. the serum esRAGE level could be a useful risk marker for some life-style related deseases.

在本研究中，我们发现了一种新的糖基化终末产物（AGE），其在糖尿病患者血清中的水平升高，确实与其细胞受体结合并诱导细胞内信号，我们还鉴定了一种新的RAGE剪接变体-内源性分泌型糖基化终末产物（ESG1）-并发现该变体对新的AGE诱导的血管损伤具有保护作用。同时发现血清雌二醇水平与生活方式相关疾病的易感性有显著相关性。(1)我们证明，新的AGE物种，这是通过孵育牛血清白蛋白与甘油醛或乙醇醛，强烈结合到细胞的表面等离子体共振方法计算的解离常数相当。(2)我们将新型AGEs的结合区域定位在其N-末端的菊糖蛋白V-结构域样区域。(3)我们证明，新AGEs与血管紧张素Ⅱ的相互作用激活了MAP激酶信号通路，并诱导了培养的人内皮细胞中V CAM-1的表达。(4)我们建立了β-淀粉样蛋白基因敲除小鼠，并证明了在缺乏β-淀粉样蛋白的情况下，糖尿病肾病的发展被显著抑制。(5)我们从人内皮细胞中分离到一种新的剪接变体，它缺乏跨膜结构域，并从细胞中分泌出来，并将这种新变体命名为内源性分泌型β-内酰胺酶（endogenous secretory β-内酰胺酶）。(6)此外，我们还发现，艾司匹林对新型AGEs诱导的血管损伤具有保护作用，其机制可能是通过细胞外捕获AGEs而实现的。(7)本文建立了艾司氯胺酮酶联免疫吸附试验（ELISA）体系，并对生活方式相关疾病患者血清中艾司氯胺酮水平进行了检测。同时发现血清雌二醇水平与生活方式相关疾病的易感性有显著相关性，提示血清雌二醇水平与生活方式相关疾病的易感性密切相关。血清雌二醇水平可作为生活方式相关疾病的危险指标。