平滑肌中LKB1在抗腹主动脉瘤形成中的作用及其机制研究

腹主动脉瘤是指腹主动脉局部梭形或囊性膨胀，管腔内径超过正常值50%的一种病理状态,瘤体破裂可导致病人的突发死亡。因此，阐明腹主动脉瘤的发生机制并寻找有效的干预措施非常必要。肝激酶B1（LKB1）作为肿瘤抑制因子，在腹主动脉瘤中的作用还不清楚。我们前期工作首次发现，在小鼠平滑肌中特异性敲除LKB1后促进了血管紧张素II诱导的腹主动脉瘤形成。同时，LKB1敲除后增加了血管紧张素II诱导的基质金属蛋白酶2（MMP2）的表达，LKB1还可以和MMP2的转录因子-特化蛋白1（Sp1）结合。据此我们设想，LKB1可能通过与Sp1竞争性结合来抑制MMP2的表达，进而抑制腹主动脉瘤的形成。本课题拟运用多种实验方法，利用平滑肌特异性敲除LKB1小鼠，在细胞和动物水平上探讨LKB1调节腹主动脉瘤形成的机制，为开发防治腹主动脉瘤的药物提供新靶点。

Abdominal aortic aneurysm (AAA) is characterized by permanent, localized dilation of the abdominal aorta exceeding the normal diameter by more than 50%. The rapid rupture of AAA results in the sudden death of patients. Thus, it is necessary to elucidate the pathogenesis of AAA and find out the effective interventions. Live Kinase B1 (LKB1) is a tumor suppressor; however, the roles of LKB1 in the pathogenesis of AAA are not clear. Our preliminary studies showed smooth muscle-specific LKB1 knockout mice promoted Angiotensin II (AngII)-induced AAA formation. Furthermore, LKB1 deficiency increased AngII-induced MMP2 expression. Besides, LKB1 can bind with the MMP2 transcription factor, specificity protein 1 (Sp1). We therefore hypothesized that LKB1 inhibits MMP2 expression through competitive binding with Sp1, resulting in reduced AAA formation. To prove this hypothesis, this study will utilize smooth muscle-specific LKB1 knockout mice to explore the mechanism by which LKB1 regulates AAA formation in both cellular and animal levels, thus to provide the new targets for finding some new effective drugs to prevent AAA.