Innovative approaches to gauge progression of Sturge-Weber Syndrome

本RDCRC提案重点关注三种相对罕见的血管畸形， 从生物机制的角度来看，资源密集型的有效管理和严重的可能性很高 神经系统疾病每种疾病的特点是发展了一个独特的类别的血管 畸形和独特的临床和表型结局谱，生物学风险因素是 要么不为人知，要么完全不为人知。确定与疾病有关的风险因素 进展对于患者监测和优化管理具有直接意义。 此外，虽然没有针对这些疾病的特定医学疗法，但适当的治疗（疗效） 试验将需要进行风险分层以进行选择，并需要进行试验开发的替代结局。 总体努力的重点是建立研究级、关系型、可扩展的临床数据库， 进行观察性或干预性试验。此外，我们将确定疾病进展的新标志物。 这一共同努力将促进新的方法来诊断，预防和治疗这三种罕见的 疾病，提供了新的风险分层方法，将适用于未来的临床试验。三 项目在这些共同的目标和目的中相互协同，它们使用共同的基础设施， 要素，以及调查人员重叠但互补的专业知识。 对于Sturge-Weber综合征（SWS）项目，我们的数据库将收集全国范围内的SWS患者， 他们在斯特奇-韦伯基金会（Sturge-Weber Foundation）卓越中心（Centers of Excellence）工作。因此，我们的数据库将是第一个 具有纵向临床数据的国家SWS数据库。此外，我们还将研究尿生物标志物， 血管生成作为SWS疾病进展和严重程度的潜在预测因子。我们的最终目标是 发现该综合征的分子遗传基础，从一个长期存在的假设开始， 由鲁道夫·哈普20年前，但未经测试，直到现在由于技术障碍。Happle提出SWS是 由体细胞突变引起的一种关键基因突变，其中不能通过种系传递。我们 基于这一假设，我提出，体细胞突变可能位于编码一种关键的 血管生成因子在SWS受累和未受累组织中使用高分辨率SNP基因分型 患者，我们提出了一个系统的方法来定位和识别SWS的致病基因。的 SWS的分子遗传病因学的阐明将为未来的发展提供新的途径， 疗法

This RDCRC proposal focuses on three relatively rare vascular malformations that are poorly understood in terms of biological mechanisms, resource-intensive to manage effectively and with high probability of serious neurological morbidity. Each disease is characterized by the development of a distinct category of vascular malformations and a unique spectrum of clinical and phenotypic outcomes, for which biological risk factors are either poorly understood or completely unknown. The identification of such risk factors that relate to disease progression would be of immediate significance for patient surveillance and for optimizing management. Further, although there are no specific medical therapies for these diseases, appropriate treatment (efficacy) trials will require risk stratification for selection and surrogate outcomes for trial development. The general effort is focused on the establishment of research grade, relational, scalable clinical databases to conduct observational or interventional trials. Further, we will identify novel markers for disease progression. The combined effort will foster new approaches to the diagnosis, prevention, and treatment of these three rare diseases, providing novel means of risk stratification that will be applicable to future clinical trials. The three projects synergize with one another in these common goals and objectives, their use of common infrastructure elements, and overlapping but complementary expertises of the investigators. For the Sturge-Weber Syndrome (SWS) project, our database will be capture SWS patients across the nation as they are seen at Sturge-Weber Foundation (SWF) Centers of Excellence. Thus, our database will be the first national SWS database with longitudinal clinical data. In addition, we will investigate urine biomarkers of angiogenesis as potential predictors of SWS disease progression and severity. Our final aim will attempt to discover the molecular genetic basis for the syndrome, starting from a long-standing hypothesis first formulated by Rudolf Happle 20 years ago, but untested until now due to technical hurdles. Happle proposed that SWS is caused by somatic mutation in a critical gene mutations in which cannot be passed through the germline. We build on this hypothesis to propose that the somatic mutation might lie within a gene encoding a critical angiogenesis factor. Using high resolution SNP genotyping in affected and unaffected tissue from SWS patients, we propose a systematic approach to mapping and identifying the causative gene(s) for SWS. The illumination of the molecular genetic etiology of SWS will suggest new avenues for future development of therapy.