Molecular pathogenesis and treatment of brain arteriovenous malformation

脑动静脉畸形的分子发病机制及治疗

• 批准号: 8269939
• 负责人: Rong Wang
• 金额: $ 29.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269939
• 关键词: Adult; Affect; Animals; Area; Arteries; Arteriovenous malformation; Base of the Brain; Behavior; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Caliber; Cells; Cellular Morphology; Cephalic; Cerebrum; Custom; Data; Development; Disease; Endothelial Cells; Endothelium; Epilepsy; Family member; Genes; Genetic; Human; Image; Imaging technology; Knowledge; Lateral; Lesion; Life; Ligands; Mammals; Mediating; Mediator of activation protein; Microscope; Modeling; Molecular; Morphology; Mus; Neurologic Dysfunctions; Neurologic Symptoms; Pathogenesis; Pathology; Pathway interactions; Photons; Physiologic arteriovenous anastomosis; Recovery; Reporting; Repression; Research; Resolution; Role; Rupture; Signal Transduction; Stroke; Structure; Technology; Tetanus Helper Peptide; Time; Transgenic Mice; Vascular Endothelial Growth Factors; Veins; Venous; Work; angiogenesis; capillary; design; effective therapy; human disease; innovation; mouse model; new growth; new therapeutic target; notch protein; public health relevance; research study; technological innovation; transmission process

DESCRIPTION (provided by applicant): Brain arteriovenous malformations (BAVMs) can cause stroke and epilepsy and have no effective treatment. BAVMs are abnormal arteriovenous (AV) shunts that are not believed to regress spontaneously, but rather are prone to dangerous rupture. The cellular and molecular basis of BAVM pathogenesis remains enigmatic. Our long-term objectives are to elucidate the mechanisms of BAVM pathogenesis and to identify novel therapeutic targets to ameliorate this disease. Our general strategy is to take a cross-disciplinary approach fusing cutting-edge mouse genetics and imaging technologies to determine the function of critical molecular pathways that normally regulate AV differentiation, such as Notch signaling, in the pathogenesis of BAVM. We have reported a faithful transgenic mouse model of BAVMs, in which expression of constitutively-active Notch4 (Notch4*) specifically in endothelium elicits hallmarks of BAVMs in immature mice. Furthermore, the areas within the developing brain which grow most rapidly, likely the most angiogenic, were most susceptible to Notch4* effects, suggesting that angiogenesis underlies BAVM formation. Repression of Notch4* expression in severely affected mice resulted in a reversal of neurologic symptoms and recovery from the illness, suggesting that BAVM-like lesions can regress in animals when the molecular cause is removed. We have also reported that Notch activity is increased in the endothelium of human BAVMs, suggesting that Notch signaling may act as a molecular mediator in the human disease. Here we hypothesize that Notch4* during angiogenesis inhibits a capillary number increase, thus promoting the enlargement of capillary diameter, which initiates and sustains AV shunts that catalyze BAVM formation. Our specific aims are designed to elucidate the mechanisms of Notch4*-mediated onset, progression, and regression of BAVM-like lesions in mice. We will combine our mouse model of BAVM with advanced 2-photon imaging to obtain 4D vascular morphology at cellular resolution and blood velocity data in living brains. Our custom-built 2-photon microscope, optimal for cerebral vascular imaging, makes this innovative study possible. Aim1 Examine the angiogenic mechanism by which Notch4* elicits BAVM-like lesions in mice. Aim2 Examine lateral induction as a potential mechanism by which Notch4* propagates Notch signaling in cerebral endothelium. Aim3 Determine the cellular mechanism underlying the regression of AV shunting upon Notch4* repression. Successful completion of this study will conceptually advance our understanding of the cellular and molecular mechanisms of BAVM pathogenesis and help establish new paradigms in the knowledge and treatment of BAVMs. Our establishment of 2-photon high resolution imaging to study BAVM development in living animals will be a major technological innovation for BAVM research at large. PUBLIC HEALTH RELEVANCE: Brain arteriovenous malformations (BAVMs) are abnormal connections between arteries and veins that can cause stroke and epilepsy. There is currently no effective treatment for BAVMs, which are conventionally believed to not regress, although recent evidence suggests regression is possible. This proposal is designed to determine the molecular pathways underlying BAVM formation and regression, with the hope of identifying novel therapeutic targets to treat this disease.

描述（申请人提供）：脑动静脉畸形（BAVM）可引起中风和癫痫，且尚无有效治疗方法。 BAVM 是一种异常的动静脉 (AV) 分流，据信不会自行消退，而是容易发生危险的破裂。 BAVM 发病机制的细胞和分子基础仍然是个谜。我们的长期目标是阐明 BAVM 的发病机制并确定新的治疗靶点来改善这种疾病。我们的总体策略是采用跨学科方法，融合尖端小鼠遗传学和成像技术，以确定通常调节 AV 分化的关键分子途径（例如 Notch 信号传导）在 BAVM 发病机制中的功能。我们报道了一种忠实的 BAVM 转基因小鼠模型，其中在内皮细胞中特异性表达组成型活性 Notch4 (Notch4*)，从而在未成熟小鼠中引发 BAVM 的特征。此外，发育中的大脑中生长最快的区域（可能是血管生成最多的区域）最容易受到 Notch4* 效应的影响，这表明血管生成是 BAVM 形成的基础。在严重受影响的小鼠中抑制 Notch4* 表达可导致神经系统症状逆转并从疾病中恢复，这表明当分子原因被消除时，BAVM 样病变可以在动物中消退。我们还报道了人类 BAVM 内皮细胞中的 Notch 活性增加，这表明 Notch 信号传导可能充当人类疾病的分子介质。在这里，我们假设血管生成过程中的 Notch4* 抑制毛细血管数量增加，从而促进毛细血管直径扩大，从而启动和维持催化 BAVM 形成的 AV 分流。我们的具体目标是阐明 Notch4* 介导的小鼠 BAVM 样病变的发生、进展和消退机制。我们将把 BAVM 小鼠模型与先进的 2 光子成像相结合，以获得活体大脑中细胞分辨率的 4D 血管形态和血流速度数据。我们定制的 2 光子显微镜最适合脑血管成像，使这项创新研究成为可能。目标 1 检查 Notch4* 在小鼠中引发 BAVM 样病变的血管生成机制。目标 2 检查横向诱导作为 Notch4* 在脑内皮细胞中传播 Notch 信号传导的潜在机制。目的3 确定 Notch4* 抑制后 AV 分流回归的细胞机制。这项研究的成功完成将在概念上增进我们对 BAVM 发病机制的细胞和分子机制的理解，并有助于建立 BAVM 知识和治疗的新范例。我们建立 2 光子高分辨率成像来研究活体动物 BAVM 的发育，这将是整个 BAVM 研究的一项重大技术创新。 公共卫生相关性：脑动静脉畸形 (BAVM) 是动脉和静脉之间的异常连接，可导致中风和癫痫。目前，BAVM 尚无有效治疗方法，传统上认为 BAVM 不会消退，但最近的证据表明，BAVM 可能会消退。该提案旨在确定 BAVM 形成和消退的分子途径，希望找到治疗这种疾病的新治疗靶点。