Integrative Study of Brain Vascular Malformations

脑血管畸形是一种罕见但重要的中风病因。临床上，一个重要的亚型是脑动静脉畸形（AVM）。目前未知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。了解导致适当中枢神经系统血管发育和完整性的信号是开发相关治疗方法以预防这些疾病出血的最有可能的方法。该提案的一个统一主题是一个垂直整合的程序，可以将临床观察与潜在遗传和细胞间信号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，因此包含与项目相关的信号通路。项目2 （Hashimoto）研究了由基质金属蛋白酶（MMP）活性和炎症活性引起的大血管重构。项目3 （Boudreau）关注同源盒基因，这是调控细胞外基质和血管生成的主要调控机制；这个项目的重点是HOX A5的抗血管生成特性，我们发现在人类BAVM组织中缺乏HOX A5。Project 4 （Nishimura）研究了星形胶质细胞-内皮细胞相互作用在脑血管内稳态关键信号通路中的作用-整合素介导的TGF-？TGF - ?信号通路与已知的唯一可遗传的AVM形式有关，即遗传性出血性毛细血管扩张。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）是临床数据收集、有组织的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、大动脉血流负荷和人到啮齿动物的组织移植；作为人体外科标本组织库的中心。

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.