Brain Vascular Malformation Consortium: Predictors of clinical course

描述（由申请人提供）：一个多学科、跨机构的研究者小组，长期对脑血管畸形感兴趣，建议建立RDCRC。研究的疾病是常见的西班牙裔突变家族性海绵状血管畸形（CCM）、Sturge-Weber综合征（SWS）和遗传性出血性毛细血管扩张症（HHT）中的脑动静脉畸形（BAVM）。这三个项目将侧重于（a）与RDCRN DMCC合作，建立可扩展的关系数据库，以促进观察性研究和临床试验;以及（B）开发具有近期潜力的疾病进展标志物，以帮助诊断和临床试验开发。CCM的目标包括使用全基因组关联方法在横断面和纵向研究设计中鉴定疾病进展的遗传标记。SWS的目的是使用尿排泄的血管生成介质作为疾病进展的标志物。此外，我们将建立体细胞突变作为一个潜在的疾病机制，着眼于适应这些知识到生物标志物的策略。HHT的目的包括使用血管结构特征和炎症基因的遗传变异，在横断面和纵向研究设计中定量估计颅内出血（ICH）风险。试点项目将评估疾病的新治疗策略，包括在SWS中使用阿司匹林和在出血性血管畸形中使用四环素类药物。我们将利用加州大学旧金山分校、杜克大学、新墨西哥州、肯尼迪克里格大学和多伦多大学的CTSA或GCRC，并制定详细的计划，培训新的研究人员进行罕见病的临床研究。三个国际患者支持组织（PSOs）-血管瘤联盟，Sturge Weber基金会，HHT基金会国际-将积极参与。通过DMCC，我们将开发一个网站，作为基于网络的数据输入的门户，并为患者，家属和专业人员提供广泛的信息。我们将利用在SWS和HHT建立的卓越中心网络来识别患者。这RDCRC将提供一个急需的和宝贵的资源，为临床神经血管社区的研究，这三种疾病。公共卫生相关性：脑血管畸形是资源密集型的有效管理，并有很高的概率严重的神经系统疾病。目前缺乏针对这些疾病的具体治疗方法。确定进展标志物将改善患者监测和优化管理，治疗试验将需要进行风险分层以进行选择，并为试验开发提供替代结局。

DESCRIPTION (provided by applicant): A multidisciplinary, inter-institutional group of investigators with long-standing interest in brain vascular malformations proposes to establish a RDCRC. The diseases of study are common Hispanic mutation familial Cavernous Malformations (CCM), Sturge-Weber Syndrome (SWS) and Brain Arteriovenous Malformation (BAVM) in Hereditary Hemorrhagic Telangectasia (HHT). The three projects will focus on (a) establishment of scalable, relational databases to facilitate observational studies and clinical trials, working with the RDCRN DMCC; and (b) development of markers for disease progression with near-term potential for aiding prognostication and clinical trial development. The aims for CCM include identification of genetic markers for disease progression in cross-sectional and longitudinal study designs using a Genome-Wide Association approach. The aims for SWS are to use urinary excretion of angiogenic mediators as markers for disease progression. Further, we will establish somatic mutations as an underlying disease mechanism with an eye towards adapting such knowledge into a biomarker strategy. The aims for HHT include quantitative estimation of intracranial hemorrhage (ICH) risk in cross-sectional and longitudinal study designs, using both angioarchitectural features and genetic variation in inflammatory genes. Pilot projects will evaluate novel treatment strategies for the diseases, including the use of aspirin in SWS and tetracycline-class agents in hemorrhagic vascular malformations. We will utilize CTSAs or GCRCs at UCSF, Duke, New Mexico, Kennedy Krieger and Univ. Toronto, with a detailed program for training new investigators in clinical research on rare diseases. Three international Patient Support Organizations (PSOs)-Angioma Alliance, Sturge Weber Foundation, HHT Foundation International-will actively participate. With the DMCC, we will develop a website as a portal for web-based data entry and include a wide range of information for patients, families and professionals. We will utilize a network of established Centers of Excellence in SWS and HHT to identify patients. This RDCRC will provide a much-needed and valuable resource for the clinical neurovascular community for the study of these three disorders. PUBLIC HEALTH RELEVANCE: Brain vascular malformations are resource-intensive to manage effectively, and have high probability of serious neurological morbidity. Specific medical therapies for these diseases are lacking. The identification of markers for progression would improve patient surveillance and optimize management, and treatment trials will require risk stratification for selection and surrogate outcomes for trial development.