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The molecular mechanisms of initiation, progression, rupture of cerebral aneurysms and development of a preventive treatment for it

脑动脉瘤发生、进展、破裂的分子机制及其预防性治疗的开发

基本信息

批准号：
17390399
负责人：
HASHIMOTO Nobuo
金额：
$ 9.98万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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/grant/KAKENHI-PROJECT-17390399/
关键词：
cerebral aneurysm animal model IL-1β apoptosis linkage analysis TNF-α MMP TIMP

项目摘要

We induced experimentally cerebral aneurysms in rats and mice.Immunohistochemistry and RT-PCR showed the upregulated expression of IL-1β mainly in medial smooth muscle cells. In IL-1β deficient mice, the ratio of advanced aneurysms was significantly reduced and the number of apoptotic cells in aneurysmal walls decreased. These data suggested that IL-1β promoted the progression of cerebral aneurysms by inducing apoptosis in smooth muscle cells.Immunohistochemistry and RT-PCR showed the expression of MMP-2 and MMP-9 increased in aneurysmal walls with aneurysm progression. In the early stage of aneurysm formation, macrophages accumulated into aneurysmal walls and secreted MMP-2 and-9. The treatment with a selective inhibitor of MMP-2 and-9, Tolylsam, significantly decreased the ratio of advanced aneurysms. These data indicated that MMP-2 and-9 secreted by macrophages promoted the progression of aneurysms.In RT-PCR, the expression of endogenous inhibitor of MMPs, TIMP-1 and-2, increased in the early stage of aneurysm formation but not in the late stage, making the ratio of MMP/TIMP elevated in advanced aneurysms. In Both TIMP-1 and TIMP-2 deficiency mice, the progression of cerebral aneurysms was promoted, demonstrating the suppressive role of TIMP-1 and-2 in aneurysm progression.In a linkage analysis of 24 families with cerebral aneurysms, TNF receptor superfamily 13B was proved to be a susceptible gene of human cerebral aneurysm.

建立大鼠和小鼠实验性脑动脉瘤模型，免疫组织化学和RT-PCR法显示IL-1β表达上调，主要分布在中膜平滑肌细胞。IL-1β缺陷小鼠进展期动脉瘤发生率显著降低，瘤壁细胞凋亡数减少。免疫组织化学和逆转录聚合酶链式反应显示，随着动脉瘤的进展，β和MMP2、MMP9的表达增加。在动脉瘤形成的早期，巨噬细胞聚集在动脉瘤壁上，分泌基质金属蛋白酶-2和-9。使用基质金属蛋白酶-2和-9的选择性抑制剂Tolylsam治疗，显著降低了晚期动脉瘤的比率。RT-PCR结果显示，内源性MMPs抑制因子TIMP-1和TIMP-2在动脉瘤形成早期表达增加，而在晚期表达增加，使进展期动脉瘤中MMPs/TIMP比值升高。在TIMP-1和TIMP-2缺乏的小鼠中，TIMP-1和TIMP-2缺陷小鼠都促进了脑动脉瘤的进展，证实了TIMP-1和TIMP-2在动脉瘤进展中的抑制作用。在24个脑动脉瘤家系的连锁分析中，肿瘤坏死因子受体超家族13B被证明是人脑动脉瘤的易感基因。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting

DOI：
10.1136/jnnp.2006.096040
发表时间：
2006-09-01
期刊：
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
影响因子：
11
作者：
Mineharu, Y.;Takenaka, K.;Koizumi, A.
通讯作者：
Koizumi, A.

Association analysis of common variants ELN, NOS2A, APOE, and ACE2 to intracranial aneurysms.

常见变异 ELN、NOS2A、APOE 和 ACE2 与颅内动脉瘤的关联分析。

DOI：
发表时间：
2006
期刊：
Stroke 37・5
影响因子：
0
作者：
Date;I;Date I;Aoki T et al.;Aoki T et al.;Mineharu Y et al.;Sadamasa N et al.;Aoki T et al.;Aoki T et al.;Sadamasa N et al.;Aoki T;Aoki T;Mineharu Y;Inoue S;Moriwaki T et al.;Mineharu Y et al.
通讯作者：
Mineharu Y et al.

Macrophage-derived matrix metalloproteinase-2 and-9 promote the progression of cerebral aneurysms in rats

DOI：
10.1161/01.str.0000252129.18605.c8
发表时间：
2007-01-01
期刊：
STROKE
影响因子：
8.3
作者：
Aoki, Tomohiro;Kataoka, Hiroharu;Hashimoto, Nobuo
通讯作者：
Hashimoto, Nobuo

Combination of linkage and association studies for brain arteriovenous malformation

DOI：
10.1161/01.str.0000260094.03782.59
发表时间：
2007-04-01
期刊：
STROKE
影响因子：
8.3
作者：
Inoue, Sumiko;Liu, Wanyang;Koizumi, Akio
通讯作者：
Koizumi, Akio

Search on chromosome 17 centromere reveals TNFRSF13B as a susceptibility gene to intracranial aneurysm.

对 17 号染色体着丝粒的搜索显示 TNFRSF13B 是颅内动脉瘤的易感基因。

DOI：
发表时间：
2006
期刊：
Circulation 113(16)
影响因子：
0
作者：
Date;I;Date I;Aoki T et al.;Aoki T et al.;Mineharu Y et al.;Sadamasa N et al.;Aoki T et al.;Aoki T et al.;Sadamasa N et al.;Aoki T;Aoki T;Mineharu Y;Inoue S;Moriwaki T et al.;Mineharu Y et al.;Inoue K et al.;Moriwaki T et al.;Mineharu Y et al.;Inoue K et al.
通讯作者：
Inoue K et al.