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）。目前的研究和本提案的统一主题所缺乏的是一个垂直整合的项目，该项目可以将临床特征，特别是颅内出血（ICH）的风险与潜在遗传和细胞间信号传导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讨论BAVM临床过程，以研究可预测自发性ICH风险的各种基因型。项目2（Hashimoto T）解决了人类手术组织标本中的细胞信号传导，并将模式与项目I确定的临床变量相关。项目3（Boudreau N）研究了同源异型盒基因作为细胞外基质和血管生成调节中的主要调节机制的作用。项目4（Nishimura S）研究星形胶质细胞-内皮细胞相互作用在脑中血管稳态的关键信号传导途径中的作用-整合素介导的TGF-β 1控制。数据管理核心（McCulloch CE）组织数据输入和分析。实验室核心（Yang戈伊）为项目3和4提供了一种脑血管生成的小鼠模型，并为项目1和4提供了一些实验室测定。 PPG基于三管齐下的方法：首先，必须研究疾病的临床行为，以确定可能具有生物学基础的自然趋势。这些临床行为可能与基因型改变有关。其次，需要研究患病组织的生物学特征，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，以产生合理的假设。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，以调查和识别与疾病相关的机制成分。一旦确定了这些机制成分，就可以更合理地制定制定治疗方法的策略。在这样一个三角测量的方法，有真实的承诺转化进展的创新治疗脑血管畸形。

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.