GNAQ体细胞突变通过Notch通路介导的动静脉异常在Sturge-Weber综合征血管畸形中的作用机制研究

Sturge-Weber综合征（SWS）继发性青光眼的巩膜表层存在血管畸形，该畸形的严重程度与手术预后直接相关，且随患者年龄增长，血管畸形程度加重导致巩膜静脉压升高，引起眼压升高。目前针对SWS血管畸形的发生和发展的研究仍是空白。我们率先发现SWS的巩膜表层血管存在GNAQ体细胞突变，且过表达该突变的血管内皮细胞系的Notch通路存在异常激活。由此提示GNAQ突变引起的Notch通路异常是导致SWS巩膜表层血管畸形的可能原因。本研究拟建立SWS巩膜畸形血管的miRNA图谱，通过差异基因统计分析明确不同发病阶段Notch信号通路介导血管畸形的效应分子；明确Notch信号通路在GNAQ R183Q点突变的人脐静脉内皮细胞系中的激活情况；建立Gnaq-R183Q cas9-ki(LSL)双转基因小鼠模型验证Notch通路在血管畸形形成中的作用。借此为确定SWS新的治疗靶点提供理论依据和研究基础。

There are vascular malformations in the scleral surface of secondary glaucoma in Sturge-Weber syndrome (SWS). The severity of this malformation is directly related to the prognosis of the operation. As the patient ages, the degree of vascular malformation aggravates the scleral venous pressure and causes intraocular pressure. Elevated. At present, the research on the occurrence and development of SWS vascular malformations is still blank. We are the first to find that there is a GNAQ somatic mutation in the scleral superficial blood vessels of SWS, and the Notch pathway of vascular endothelial cell lines overexpressing this mutation is abnormally activated. This suggests that the abnormal Notch pathway caused by GNAQ mutation is the possible cause of the vascular malformation of the sclera in SWS. This study intends to establish a miRNA map of SWS scleral malformation vessels, and clarify the effector molecules of Notch signaling pathway in vascular malformations at different stages of onset through statistical analysis of differential genes; clarify the role of Notch signaling pathway in human umbilical vein endothelial cell line with GNAQ R183Q point mutation Activation: Establish Gnaq-R183Q cas9-ki(LSL) double transgenic mouse model to verify the role of Notch pathway in the formation of vascular malformations. Provide a theoretical basis and research basis for determining the new therapeutic target of SWS.