CADASIL中NOTCH/NF-κB/Rho激酶通路介导的微丝骨架异常及小动脉病变机制研究

CADASIL是由NOTCH3基因突变引起的遗传性脑小血管病，其发病机制不明且缺乏有效治疗手段。课题组前期研究表明CADASIL患者存在脑小动脉血流调节功能异常，其血管平滑肌细胞存在微丝骨架异常及NOTCH通路上调介导的NF-κB激活。既往研究表明NOTCH蛋白可以通过非经典通路激活NF-κB及Rho激酶通路，且NF-κB激活可以促进Rho激酶通路活化。我们推测CADASIL中存在由NOTCH/NF-κB/Rho激酶通路介导的微丝骨架异常，最终导致血管平滑肌细胞及小动脉功能异常。本研究中我们将利用患者组织、小鼠模型及诱导多能干细胞模型分别从组织和细胞层面验证上述假说，同时借助Hela细胞从分子层面深入研究NOTCH、NF-κB及Rho激酶通路相互调控的机制，最后在小鼠模型及诱导多能干细胞模型中应用小分子抑制剂改善血管平滑肌细胞及小动脉功能，为CADASIL发病机制和治疗方法的研究提供思路。

CADASIL is a hereditary cerebral small vascular disease caused by NOTCH3 gene mutations. Its pathogenesis is unknown and there is no effective treatment. Our previous study showed that the blood auto-regulation function of cerebral small arteries was abnormal in patients with CADASIL. In addition, there were microfilaments disorganization and NF-κB activation mediated by up-regulation of NOTCH pathway in CADASIL vascular smooth muscle cells. Previous studies have shown that NOTCH can activate NF-κB and Rho kinase pathway through non-canonical pathway. And activated NF-κB can promote the activation of Rho kinase pathway. Therefore, we speculate that there are microfilaments abnormalities mediated by NOTCH/NF-κB/Rho kinase pathway in CADASIL, which further leads to dysfunction of vascular smooth muscle cells and cerebral small arteries. In this study, we will use patient tissues, mouse model and induced pluripotent stem cell model to verify the above hypothesis from the tissue and cell level respectively. At the same time, Hela cells will be used to further study the mechanism of mutual regulation among NOTCH, NF-κB and Rho kinase pathways. Finally, we will try to use inhibitors to improve the function of vascular smooth muscle cells and cerebral small arteries in mouse model and induced pluripotent stem cell model. Our research will provide clues for the future research of disease pathogenesis and treatments.