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（由申请人提供）：脑动力畸形（BAVM）可能引起中风和癫痫病，没有有效的治疗。 Bavms是异常的动静脉（AV）分流器，不认为自发地退回，而是容易发生危险破裂的分流。 BAVM发病机理的细胞和分子基础仍然神秘。我们的长期目标是阐明BAVM发病机理的机制，并确定新的治疗靶标以改善该疾病。我们的一般策略是采用跨学科方法融合尖端的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的功能，例如Notch信号，在BAVM的发病机理中。我们报道了BAVM的忠实转基因小鼠模型，其中在内皮中特别在未成熟小鼠中特别在内皮中表达了bavms的标志。此外，发育中的大脑中生长最快的区域，可能是最具血管生成的区域，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。严重影响小鼠中Notch4*表达的抑制导致神经系统症状和从疾病中恢复的逆转，这表明当分子原因去除分子原因时，类似BAVM的病变会在动物中退缩。我们还报道说，人类BAVM的内皮中的缺口活性增加，这表明Notch信号传导可能是人类疾病中的分子介体。在这里，我们假设在血管生成期间Notch4*抑制了毛细血管数的增加，从而促进了毛细血管直径的扩大，从而启动和维持了催化BAVM形成的AV分流。我们的具体目的旨在阐明小鼠中BAVM样病变的Notch4*介导的发作，进展和回归的机制。我们将将BAVM的小鼠模型与高级2光子成像结合在一起，以在活大脑中的细胞分辨率和血速数据下获得4D血管形态。我们定制的2光子显微镜（最适合脑血管成像）使这项创新的研究成为可能。 AIM1检查Notch4*在小鼠中引起BAVM样病变的血管生成机制。 AIM2将横向诱导作为一种潜在机制，通过该机制，Notch4*在脑内皮中传播Notch信号。 AIM3确定在Notch4*抑制作用时AV回归的基础的细胞机制。这项研究的成功完成将在概念上促进我们对BAVM发病机理的细胞和分子机制的理解，并有助于在BAVM的知识和治疗中建立新的范式。我们建立了2光量高分辨率成像来研究活动物的BAVM开发，这将是BAVM研究的主要技术创新。 公共卫生相关性：大脑动脉畸形（BAVM）是动脉和静脉之间的异常联系，可能引起中风和癫痫病。目前尚无对BAVM的有效治疗方法，尽管最近有证据表明可以进行回归，但通常认为这是不退缩的。该建议旨在确定BAVM形成和回归的分子途径，希望鉴定出新的治疗靶标的以治疗该疾病。