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: 7987203
• 负责人: Rong Wang
• 金额: $ 30.14万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987203
• 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)可导致中风和癫痫，目前还没有有效的治疗方法。BAVM是一种异常的动静脉分流，不被认为是自发退行性的，而是容易发生危险的破裂。脑动静脉畸形发病机制的细胞和分子基础仍是个谜。我们的长期目标是阐明脑动静脉畸形的发病机制，并寻找新的治疗靶点来改善这种疾病。我们的总体策略是采用融合尖端小鼠遗传学和成像技术的跨学科方法来确定正常调节房室分化的关键分子途径的功能，例如Notch信号在BAVM的发病机制中的作用。我们报道了一种忠实的BAVMS转基因小鼠模型，在该模型中，内皮细胞特异性表达的结构性活性Notch4(Notch4*)在未成熟小鼠中引发了BAVMS的特征。此外，发育中的大脑中生长最快、血管生成最多的区域最容易受到Notch4*效应的影响，这表明血管生成是脑动静脉畸形形成的基础。在受严重影响的小鼠中抑制Notch4*的表达导致神经系统症状的逆转和疾病的康复，这表明当分子原因被移除时，BAVM样病变可以在动物身上消退。我们还报道了人BAVM的内皮细胞中Notch活性增加，提示Notch信号可能在人类疾病中起到分子介质的作用。在这里，我们假设在血管生成过程中，Notch4*抑制了毛细血管数量的增加，从而促进了毛细血管直径的扩大，从而启动并维持了催化BAVM形成的房室分流。我们的特定目的是为了阐明Notch4*介导的小鼠BAVM样病变的发生、发展和消退的机制。我们将把我们的BAVM小鼠模型与先进的双光子成像相结合，以获得细胞分辨率的4D血管形态和活体大脑的血流速度数据。我们定制的双光子显微镜是脑血管成像的最佳选择，使这项创新研究成为可能。目的研究Notch4*在小鼠中引起BAVM样损伤的血管生成机制。AIM2研究了侧向诱导作为Notch4*在脑内皮细胞中传播Notch信号的潜在机制。Aim3确定Notch4*抑制后房室分流逆转的细胞机制。这项研究的成功完成将从概念上促进我们对脑动静脉畸形发病机制的细胞和分子机制的理解，并有助于在脑动静脉畸形的认识和治疗方面建立新的范式。我们建立了双光子高分辨率成像来研究活体动物的BAVM发育，这将是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。目前还没有有效的治疗方法来治疗BAVM，传统上认为这种疾病不会消退，尽管最近的证据表明消退是可能的。该建议旨在确定脑动静脉畸形形成和消退的分子途径，希望找到治疗这种疾病的新的治疗靶点。