Pharmacotherapy for abdominal aortic aneurysm by the inhibition of c=jun N-terminal kinase

抑制c=jun N末端激酶治疗腹主动脉瘤

• 批准号: 16390365
• 负责人: AOKI Hiroki
• 金额: $ 8.45万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390365/
• 关键词: aortic aneurysm; atheroscleosis; c-Jun N-terminal kinase; JNK; animal model; therapy; JNK inhibitor; regression

Abdominal aortic aneurysm is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. Although non-surgical treatment for aortic aneurysm is much awaited, few opt ions are available because its molecular pathogenesis remains elusive. We identified JNK as a proximal signaling molecule in the pathogenesis of aortic aneurysm. Human abdominal aortic aneurysm tissue showed high level of phospho-JNK. We show that JNK programs a gene expression pattern in different cell types, which cooperatively enhances the degradation of the extracellular matrix, while suppressing biosynthetic enzymes of the extracellular matrix. Selective JNK inhibition in vivo not only prevented the development of aortic aneurysm but also caused regression of established aortic aneurysm in two mouse models. Therefore, JNK promotes abnormal extracellular matrix metabolism in the tissue of aortic aneurysm and may represent a novel therapeutic target.

腹主动脉瘤是老年人中的常见疾病，当外科治疗不适用时，会导致主动脉进行性扩张和破裂，死亡率高。虽然非手术治疗的主动脉瘤是期待已久，但很少有选择，因为它的分子发病机制仍然是难以捉摸的。我们确定JNK作为近端信号分子在主动脉瘤的发病机制。人腹主动脉瘤组织中磷酸化JNK水平高。我们表明，JNK程序的基因表达模式在不同的细胞类型，这合作增强细胞外基质的降解，同时抑制细胞外基质的生物合成酶。选择性JNK抑制在体内不仅防止了主动脉瘤的发展，但也造成了两个小鼠模型中建立的主动脉瘤消退。因此，JNK促进了主动脉瘤组织中细胞外基质的异常代谢，可能是一个新的治疗靶点。

项目成果

Identification of c-Jun N-terminal kinase as a therapeutic target for abdominal aortic aneurysm.

鉴定 c-Jun N 末端激酶作为腹主动脉瘤的治疗靶点。

• 发表时间: 2006
• 期刊: Ann N Y Acad Sci. 1085
• 作者: 佐々木;成子;Yoshimura K et al.
• 通讯作者: Yoshimura K et al.

シグナル伝達と血管疾患 : 治療標的分子同定のストラテジー

信号转导和血管疾病：识别治疗靶分子的策略

• 发表时间: 2006
• 期刊: 実験医学増刊号「分子メカニズムから解き明かす疾患のサイエンス」 24・10
• 作者: Kasuya H;Takeda S;Shimoyama S;Shikano N;Nomura N;et al.;青木浩樹
• 通讯作者: 青木浩樹

Stabilization of Extracellular Matrix Antagonizes Proinflammatory Signaling and Prevents Progression of Abdominal Aortic Aneurysm In Vivo

细胞外基质的稳定拮抗促炎信号并预防体内腹主动脉瘤的进展

• 发表时间: 2006
• 期刊: Circulation 114
• 作者: Murakami Y;Uemura K;et al.;吉村耕一
• 通讯作者: 吉村耕一

動脈瘤予防および/または治療剤

动脉瘤预防和/或治疗剂

• 发表时间: 2011

動脈瘤予防剤

动脉瘤预防剂

• 发表时间: 2004