Molecular mechanisms of cerebral aneurysmal formation

脑动脉瘤形成的分子机制

• 批准号: 13307043
• 负责人: HASHIMOTO Nobuo
• 金额: $ 33.95万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13307043/
• 关键词: cerebral aneurysmal; iNOS; endothelium; MMP; gene; 動物モデル; 血行力学的ストレス; 高血圧; ラット; マウス; hemodynamic stress

The pathogenesis of cerebral aneurysm has not been-fully understood. We have developed experimental cerebral aneurysmal models in rats and mice and analyzed expressed proteins and messenger RNAs during the process of cerebral aneurismal formation. We confirmed the decrease in eNOS in the endothelium and increase in iNOS in the smooth muscle during the process, and demonstrated that an inhibitor of iNOS and the disruption of iNOS gene inhibited the aneurysmal formation. We also demonstrated increased active MMP-2 and 9 during the process and the knockout of MMP-9 decreased the formation of cerebral aneurysm. We also detected by PCR the expression of specific molecules which are related to vascular remodeling. Finally we analyzed the candidate genes which had high linkage to aneurysmal formation in highly-aggregated Japanese families.

脑动脉瘤的发病机制尚未完全清楚。我们在大鼠和小鼠中建立了实验性脑动脉瘤模型，并分析了脑动脉瘤形成过程中表达的蛋白质和信使RNA。我们证实了在此过程中内皮细胞中eNOS的减少和平滑肌中iNOS的增加，并证明iNOS抑制剂和iNOS基因的破坏抑制了动脉瘤的形成。我们还证明了在此过程中活性MMP-2和9的增加，并且MMP-9的敲除减少了脑动脉瘤的形成。我们还通过PCR检测了与血管重塑相关的特定分子的表达。最后，我们分析了高度聚集的日本家庭中与动脉瘤形成高度相关的候选基因。

项目成果

Yamada S. et al.: "Absence of linkage of familial intracranial aneurysms to 7q11 in highly aggregated Japanese families"Stroke. 34. 892-900 (2003)

Yamada S. 等人：“在高度聚集的日本家庭中，家族性颅内动脉瘤与 7q11 缺乏联系”中风。

Kawanabe Y, Nozaki K, Hashimoto N, Masaki T: "Characterization of Ca2+ channels and G proteins involved in arachidonic acid release by endothelin-1 /endothelin A receptor"Mol Pharmacol. 64. 689-695 (2003)

Kawanabe Y、Nozaki K、Hashimoto N、Masaki T：“内皮素 1/内皮素 A 受体释放花生四烯酸所涉及的 Ca2 通道和 G 蛋白的特征”Mol Pharmacol。

Yamada S et al.: "Absence of linkage of familial intracranial aneurysms to 7q11 in highly aggregated Japanese families"Stroke. (in press). (2003)

Yamada S 等人：“在高度聚集的日本家庭中，家族性颅内动脉瘤与 7q11 缺乏联系”中风。

Kawanabe Y, Okamoto, Y, Nozaki K, Hashimoto N, Miwa S, Masaki T: "Molecular mechanism for endothelin-1-induced stress-fiber formation: analysis of G proteins using a mutant Endothelin A receptor"Molecular Pharmacol. 61. 277-284 (2002)

Kawanabe Y、Okamoto、Y、Nozaki K、Hashimoto N、Miwa S、Masaki T：“内皮素 1 诱导的应力纤维形成的分子机制：使用突变型内皮素 A 受体分析 G 蛋白”Molecular Pharmacol。

Morimoto M et al.: "Strategic medical science against brain attack"Springer-Verlag Tokyo. 294 (2002)

Morimoto M 等人：“针对脑攻击的战略医学”，Springer-Verlag 东京。