miR-29通过调控血管壁重构参与颅内动脉瘤发生的机制研究

Intracranial aneurysm is one of the most commonly cerebrovascular diseases that make serious threat to human life. Vascular remodeling and extracellular matrix play important roles in the development of intracranial aneurysm, while the understanding of its cellular and molecular mechanisms are limited. By the analysis of miRNA expression profiling and microarray of biological reaction pathways, we find that the expression of miR-29 family was significantly down regulated and its targeted genes are also abnormally expressed when compared to the normal tissues in our previous study, which implies that miR-29 may participate in the formation of intracranial aneurysms. Furthermore, the targeted genes of miR-29 are most related to the vascular and extracellular matrix remodeling. This proposal will not only focus on the dynamic changes of miR-29 and its targeted genes in the development of intracranial aneurysm, but also clarifying its role in the regulatory mechanisms of cerebral vascular endothelial cells, vascular smooth muscle cells and extracellular matrix signal transduction. This study will provide novel strategies and targets for the prevention and treatment of intracranial aneurysm.

颅内动脉瘤是一种严重威胁生命安全的常见脑血管病。在颅内动脉瘤发生、发展过程中，血管壁的重建与细胞外基质的重构异常发挥了关键作用，但目前对这一疾病产生的细胞和分子机制的认识仍十分有限。在我们前期工作中，通过miRNA表达谱分析和mRNA芯片结合生物反应路径分析发现相较于正常组织，miRNA家族成员miR-29在颅内动脉瘤中表达发生下调，同时其靶基因也存在表达异常。提示了miR-29家族可能在颅内动脉瘤的发生和发展过程中发挥了作用，而且miR-29的靶基因与血管重建以及细胞外基质重建密切相关。本课题将重点研究miR-29及其靶基因在颅内动脉瘤发生和发展过程中的动态变化以及上下游调控机制，探索其在调控脑动脉血管内皮、平滑肌细胞及细胞基质生物学特性中的信号转导机制，鉴定出起主导作用的关键分子，为颅内动脉瘤的病因分析、预防、诊断和治疗提供新的思路。

通过miRNA表达谱分析和mRNA芯片结合生物反应路径分析发现相较于正常组织，miRNA家族成员miR-29在颅内动脉瘤中表达发生下调，同时其靶基因也存在表达异常。提示了miR-29家族可能在颅内动脉瘤的发生和发展过程中发挥了作用，而且miR-29的靶基因与血管重建以及细胞外基质重建密切相关。本课题重点研究miR-29及其靶基因在颅内动脉瘤发生和发展过程中的动态变化以及上下游调控机制，通过MMP活性检测、免疫印迹、PCR、转染等手段探索其在调控脑动脉血管内皮、平滑肌细胞及细胞基质生物学特性中的信号转导机制，其中转染miR-29的人平滑肌细胞系MMP活性上升，COL1A1、COL3A1、COL5A、elastin（ELA）、fibrillin-1（FBN1)均在转录及表达层面上有所下降，miR-29家族中miR-29c活性最强，为颅内动脉瘤的病因分析、预防、诊断和治疗提供新的思路。