Integrative Study of Brain Vascular Malformations

描述（由申请人提供）：脑血管畸形约占中风综合征的10%。临床上一个重要的亚型是脑动静脉畸形（BAVM）。当前研究和本提案的统一主题所缺乏的是一个垂直整合的程序，可以将临床特征，特别是颅内出血（ICH）的风险，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。项目一（Young WL）将通过横断面和纵向队列设计来研究可以预测自发性脑出血风险的各种基因型，以解决BAVM的临床过程。项目2 （Hashimoto T）解决了人类手术组织标本中的细胞信号，并将模式与项目1确定的临床变量联系起来。项目3 （Boudreau N）研究了同源盒基因在细胞外基质和血管生成调控中的主要调控机制的作用。Project 4 （Nishimura S）研究了星形胶质细胞-内皮细胞相互作用在脑整合素介导的TGF-fl控制中血管稳态的关键信号通路中的作用。数据管理核心（McCulloch CE）组织数据输入和分析。实验室核心（Yang GY）为项目3和4提供了一个小鼠脑血管生成模型，并为项目1和4提供了一些实验室分析。

DESCRIPTION (provided by applicant): Vascular malformations of the brain account for roughly 10% of stroke syndromes. Clinically, an important subtype is brain arteriovenous malformation (BAVM). What is lacking in current research and the unifying theme of this proposal is a vertically integrated program that can relate clinical characteristics, notably risk of intracranial hemorrhage (ICH), with various aspects of the underlying genetic and cell-to cell signaling abnormalities. Project I (Young WL) will address BAVM clinical course in a cross-sectional and longitudinal cohort design to study various genotypes that can predict risk of spontaneous ICH. Project 2 (Hashimoto T) addresses cellular signaling in human surgical tissue specimens and relates patterns to Project I clinical variables determined. Project 3 (Boudreau N) examines the role of homeobox genes as master regulatory mechanisms in the regulation of extracellular matrix and angiogenesis. Project 4 (Nishimura S) investigates the role of astrocyte-endothelial cell interaction in a key signaling pathway for vascular homeostasis in the brain - integrin-mediated control of TGF-fl. The Data Management Core (McCulloch CE) organizes data input and analyses. The Laboratory Core (Yang GY) furnishes a murine model of brain angiogenesis for use in Projects 3 and 4, and some laboratory assays for Projects 1 and 4. The PPG is based on a three-pronged approach: first, the clinical behavior of the disease must be studied to identify natural tendencies likely to have biologic underpinning. These clinical behaviors can be associated with genotypic alterations. Second, biologic characteristics of diseased tissue need to be studied to confirm or rule out likely pathways relevant to the human disease. Such pathways need correlation to the clinical behavior of the disease to generate plausible hypotheses. Third, plausible hypotheses must be tested in animal models or cell culture systems to investigate and identify mechanistic components of relevance to the disease. Once such mechanistic components are identified, strategies to develop therapeutic approaches can be more rationally formulated. In such a triangulation of approaches, there is real promise for translational progress in the innovative therapy of brain vascular malformations.