Innovative Approaches to gauge Porgression of Sturge-Weber Syndrome

Sturge-Weber综合征（SWS）是一种罕见的先天性但散发性疾病，其特征在于面部葡萄酒胎记、脉络膜和软脑膜血管畸形、癫痫、中风样发作、头痛和认知障碍。该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，提示血管重塑在SWS中很重要。我们假设血管重塑在SWS中正在进行，是临床进展的核心，并且与最近发现的GNAQ中的致病性体细胞突变有关。SWS的致病性体细胞突变是GNAQ基因的激活突变，GNAQ基因是一种在传递G蛋白偶联受体（GPCR）信号中必不可少的鸟嘌呤核苷酸结合蛋白，其中许多对血管发育和功能至关重要。有了这些新知识，我们将研究我们的中心假设，并准备临床，生化和分子分析的治疗试验。 在项目2中，我们的数据库将继续收集全国各地的SWS患者，因为他们在Sturge-Weber基金会卓越中心被发现。该数据库是第一个具有纵向临床数据的国家SWS数据库，这项工作已经整合了七个临床研究中心。我们现在建议在多中心临床研究中采取下一步措施，进行纵向多中心临床研究，量化SWS受试者的血管重塑，开发新的生物标志物，并提出安全性药物研究作为试点项目。我们还将建立在我们的第一轮资金的显着成功，发现导致SWS的GNAQ体细胞嵌合突变，并确定这种遗传缺陷对SWS皮肤和脑组织中下游蛋白质和途径的影响。SWS分子遗传学通路的阐明将为未来治疗的发展提供新的途径。

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.