Integrative Study of Brain Vascular Malformations

脑血管畸形是一种罕见但重要的中风原因。脑动静脉畸形（AVM）是临床上的一个重要亚型。目前尚不清楚的血管生成和血管组装缺陷被认为是临床表型发展的基础。了解导致适当CNS血管发育和完整性的信号传导是开发相关治疗以预防这些疾病中出血的最可能方法。该提案的一个统一主题是一个垂直整合的计划，可以将临床观察与潜在的遗传和细胞间信号传导异常的各个方面联系起来。项目1（Young）是一项临床研究，将使用全基因组关联方法识别与AVM易感性相关的新型候选遗传变异，因此涵盖了项目相关的信号通路。项目2（Hashimoto）解决了由于基质金属蛋白酶（MMP）活性和炎症活性引起的大血管重塑。项目3（Boudreau）涉及同源异型盒基因，这是在细胞外基质和血管生成的调节主调节机制;该项目的重点是HOX A5的抗血管生成特性，我们发现它在人BAVM组织中缺乏。项目4（Nishimura）研究星形胶质细胞-内皮细胞相互作用在脑血管稳态关键信号通路中的作用-整合素介导的TGF-β控制; TGF-？信号传导与AVM的唯一已知的可遗传形式有关，即，遗传性出血性毛细血管扩张症这三个核心服务于所有项目。行政核心A（Young）协调PPG活动。数据管理核心B（McCulloch）作为临床数据收集、组织数据输入和分析的中心机制。实验室核心C（Su）为实验室项目中使用的模型提供了中心实验室资源，包括小鼠血管发育不良、大动脉流量负荷和人-啮齿动物组织移植;并作为中心人类手术标本组织库。 目前，动静脉畸形的治疗是摘除性的，费用相对较高，风险很大。对疾病病理生理学的机制性洞察的改善将促进针对目前没有特异性药物治疗的疾病的新疗法和生物标志物的开发。该计划代表了临床和基础研究人员的独特耦合，沿着独特的大型临床数据库和组织库，以解决复杂而重要的临床问题。

Vascular malformations of the brain are a rare but important cause of stroke. Clinically, an important subtype is brain arteriovenous malformation (AVM). As-yet unknown defects in angiogenesis and vascular assembly are thought to undergird development of the clinical phenotype. Understanding the signaling which results in proper CNS vascular development and integrity is the likeliest approach to developing relevant therapies to prevent hemorrhage in these conditions. A unifying theme of this proposal is a vertically integrated program that can relate clinical observations to various aspects of the underlying genetic and cell-to-cell signaling abnormalities. Project 1 (Young) is a clinical investigation that will identify novel candidate genetic variants associated with AVM susceptibility using genome-wide association methods, therefore encompassing project-related signaling pathways. Project 2 (Hashimoto) addresses macrovascular remodeling due to matrix metalloprotease (MMP) activity and inflammatory activity. Project 3 (Boudreau) concerns homeobox genes, which are master regulatory mechanisms in the regulation of extracellular matrix and angiogenesis; this project focuses on the anti-angiogenic properties of HOX A5, which we have found to be deficient in human BAVM tissue. Project 4 (Nishimura) investigates the role of astrocyte-endothelial cell interactions in a key signaling pathway for cerebrovascular homeostasis- integrin-mediated control of TGF-?; TGF-? signaling is implicated in the only known heritable form of AVM, i.e., hereditary hemorrhagic telangectasias. The three cores serve all projects. The Administrative Core A (Young) coordinates PPG activities. The Data Management Core B (McCulloch) serves as the central mechanism for clinical data collection, organized data input and analyses. The Laboratory Core C (Su) furnishes a central laboratory resource for models used in the laboratory project including murine vascular dysplasia, flow loading of large arteries, and human-to-rodent tissue transplant; and serves as a central human surgical specimen tissue bank. At the present time, AVM treatment is extirpative and entails relatively high costs with significant risks. Improved mechanistic insight into the pathophysiology of the disease will facilitate development of novel therapies and biomarkers for a disease that currently has no specific medical therapy. This program represents a unique coupling of clinical and basic investigators, along with a unique, large clinical database and tissue bank, to address a complex and important clinical problem.