Innovative Approaches to gauge Porgression of Sturge-Weber Syndrome

斯特奇-韦伯综合征（SWS）是一种罕见的先天性散发疾病，其特征为面部葡萄酒型胎记、脉络膜和小脑膜血管畸形、癫痫、卒中样发作、头痛和认知障碍。这种疾病的特征是持续的血管过度生长；SWS病变组织的组织病理学研究显示血管表型和血管生成因子的异常表达。血管生成因子与临床严重程度相关，表明血管重构在SWS中很重要。我们假设血管重构在SWS中持续进行，是临床进展的核心，并且与最近发现的GNAQ致病性体细胞突变有关。SWS的致病体细胞突变是GNAQ基因的激活突变，GNAQ基因是一种鸟嘌呤核苷酸结合蛋白，在g蛋白偶联受体（gpcr）的信号传递中必不可少，其中许多对血管发育和功能至关重要。有了这些新知识，我们将调查我们的中心假设，并为临床、生化和分子分析的治疗试验做准备。

Sturge-Weber syndrome (SWS) is a rare, congenital but sporadic disease characterized by a facial port-wine birthmark, choroidal and leptomeningeal vascular malformations, epilepsy, stroke-like episodes, headache, and cognitive impairment. The disease is characterized by ongoing vascular overgrowth; histopathological studies of SWS lesion tissue show abnormal expression of vascular phenotypes and angiogenic factors. Angiogenic factors correlate with clinical severity suggesting that vascular remodeling is important in SWS. We hypothesize that vascular remodeling is ongoing in SWS, is central to the clinical progression, and is related to the recently discovered pathogenic somatic mutation in GNAQ. The causative somatic mutation for SWS is an activating mutation in the GNAQ gene, a guanine nucleotide binding protein essential in transmitting signals from G-protein coupled receptors (GPCRs), many of which are essential to vascular development and function. With this new knowledge, we will investigate our central hypotheses and prepare for treatment trials with clinical, biochemical, and molecular analyses. In Project 2, our database will continue to capture SWS patients across the nation as they are seen at Sturge-Weber Foundation (SWF) Centers of Excellence. This database is the first national SWS database with longitudinal clinical data and this effort has integrated seven clinical research centers. We now propose to take the next steps in multi-centered clinical research and engage in longitudinal multi-centered clinical research that will quantify vascular remodeling in subjects with SWS, develop new biomarkers, and propose a safety drug study as a pilot project. We will also build upon the remarkable success of our first round of funding, the discovery of the somatic mosaic mutation in GNAQ that causes SWS, and determine the impact of this genetic defect upon downstream proteins and pathways in SWS skin and brain tissue. The illumination of the molecular genetic pathways of SWS will suggest new avenues for future development of therapy.