Integrative Study of Brain Vascular Malformations

描述(申请人提供)：脑血管畸形约占中风综合征的10%。脑动静脉畸形(BAVM)是临床上的一个重要亚型。目前的研究和这项提议的统一主题所缺乏的是一个垂直整合的计划，该计划可以将临床特征，特别是颅内出血(ICH)的风险，与潜在的遗传和细胞间信号异常的各个方面联系起来。项目I(Young WL)将在横断面和纵向队列设计中探讨脑动静脉畸形的临床过程，以研究可以预测自发性脑出血风险的各种基因类型。项目2(桥本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)研究了同源框基因在调节细胞外基质和血管生成中作为主要调节机制的作用。项目4(西村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转化生长因子-β1调控中血管内稳态的关键信号通路中的作用。数据管理核心(McCulloch CE)负责组织数据输入和分析。实验室核心(杨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。 PPG基于三管齐下的方法：首先，必须研究疾病的临床行为，以确定可能有生物基础的自然倾向。这些临床行为可能与基因改变有关。其次，需要研究病变组织的生物学特征，以确认或排除与人类疾病相关的可能途径。这些途径需要与疾病的临床行为相关联，才能产生可信的假说。第三，合理的假设必须在动物模型或细胞培养系统中进行测试，以调查和确定与疾病相关的机械因素。一旦确定了这样的机械成分，就可以更合理地制定开发治疗方法的战略。在这种方法的三角划分中，在脑血管畸形的创新治疗方面取得翻译进展是有希望的。

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.