Molecular Pathogenesis of Hereditary Hemorrhagic Telangiectasia

遗传性出血性毛细血管扩张症的分子发病机制

• 批准号: 10083767
• 负责人: Rong Wang
• 金额: $ 43.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10083767
• 关键词: 3-Dimensional; ACVRL1 gene; Activin Receptor; Alleles; Animal Model; Arteries; Arteriovenous malformation; Bioinformatics; Blood; Blood Vessels; Blood capillaries; Brain; Brain imaging; Candidate Disease Gene; Cephalic; Characteristics; Clinical; Dangerousness; Data; Defect; Development; Disease; Disease Progression; Disease model; Dominant Genetic Conditions; Endothelial Cells; Endothelium; Etiology; Event; Expression Profiling; Functional disorder; Future; Gene Expression Profile; Genes; Genetic Diseases; Genetic Transcription; Genomics; Goals; Hereditary hemorrhagic telangiectasia; Histopathology; Human; Hypoxia; Image; Immunofluorescence Immunologic; Impairment; In Situ; Inflammation; Inherited; Intervention; Intracranial Hemorrhages; Knock-out; Knowledge; Lead; Lesion; Ligands; LoxP-flanked allele; Mediator of activation protein; Mesenchymal; Modeling; Molecular; Mus; Mutation; Neurologic; Organ; Pathogenesis; Pathology; Patients; Pattern; Perfusion; Physiologic arteriovenous anastomosis; Pre-Clinical Model; Preventive treatment; Process; Production; RNA; Research; Resolution; Retina; Scientific Advances and Accomplishments; Shunt Device; Signal Transduction; Structure; Superoxides; Techniques; Therapeutic; Time; Transforming Growth Factor beta; Veins; Work; base; bioinformatics tool; bone morphogenetic protein receptors; brain endothelial cell; clinical practice; density; design; drug candidate; genetic association; genome-wide; innovation; malformation; mouse model; neurobehavioral; new therapeutic target; novel; novel therapeutic intervention; postnatal; pre-clinical; ribosome profiling; success; therapeutic candidate; transcriptome; two-photon

PROJECT SUMMARY/ABSTRACT Arteriovenous (AV) malformations (AVMs) are vascular anomalies that shunt blood from an artery directly to a vein, causing organ dysfunction. AVM pathogenesis is poorly understood, limiting the rational design of molecular interventions. Our long-term goal is to develop better therapeutic treatments for AVMs, as current treatment options are limited and risky. Our strategy is to focus on brain AVMs (BAVMs), as they are the most dangerous AVMs, and findings in BAVM are applicable to AVMs elsewhere in the body. Most BAVMs are sporadic, but hereditary BAVMs, such as those seen in hereditary hemorrhagic telangiectasia (HHT), offer an excellent opportunity to study the molecular mechanism underlying disease processes. HHT is an autosomal dominant genetic disorder characterized by multifocal AVMs throughout the body, including the brain. Mutations in activin receptor-like kinase (ALK1) are responsible for Type 2 HHT (HHT2), which represents 25- 57% of all HHT cases. Alk1 is a type I TGFβ receptor for BMP ligands, and the mechanism through which Alk1 leads to AVMs is poorly understood. Building on our strong preliminary data, we propose to establish a novel HHT2-BAVM mouse model, with which to identify molecular regulators crucial for AVM pathogenesis, using both a targeted approach and unbiased genome-wide expression profiling. To this end, we propose to establish a much-needed robust preclinical animal model that faithfully models certain aspects of disease presentations in HHT2 patients. Existing mouse models of HHT are limited in recapitulating clinical manifestations. Using a cutting-edge strategy, we have developed a useful mouse model of HHT2-BAVM by deleting both Alk1 alleles specifically in brain endothelial cells, and have obtained strong preliminary data that this deletion results in robust BAVM, intracranial hemorrhages, and neurological consequences, without detectable defects elsewhere in the body. We will first fully characterize this model using innovative, high- resolution two-photon imaging through a cranial window to access the vasculature in live brains, achieving a 5D perspective (3D vascular structure plus blood velocity over time). W candidate molecular regulators that promote BAVM formation including AV programming, endothelial barrier, inflammation, endothelial-to-mesenchymal transition, and superoxide production in mice with Alk1 deletion in the brain endothelium. Finally, we will perform cutting-edge genomic expression profiling to elucidate Alk1 target genes, and then use bioinformatics tools to categorize identified genes based on their functional characteristics. Our proposed Aims comprise a combination of technical and conceptual innovations that will advance the knowledge of the molecular mechanisms underlying AVM formation and HHT pathogenesis. Our work will establish a robust preclinical model for these diseases, uncover new molecular mechanisms underlying the disease etiology, and impact future clinical practice for patients with HHT and BAVM. e will also investigate

项目摘要/摘要 动静脉畸形(AVM)是一种血管畸形，它将血液从动脉直接分流到血管。 静脉，导致器官功能障碍。AVM的发病机制尚不清楚，限制了合理的设计 分子干预。我们的长期目标是开发更好的治疗动静脉畸形的方法，就像目前 治疗选择有限且有风险。我们的战略是专注于脑AVM(BAVM)，因为它们是 危险的脑动静脉畸形和脑动静脉畸形的发现也适用于身体其他部位的脑动静脉畸形。大多数BAVM都是 零星的，但遗传性的BAVM，如遗传性出血性毛细血管扩张症(HHT)，提供了 这是研究疾病过程的分子机制的绝佳机会。Hht是一种常染色体 显性遗传性疾病，其特征是全身多灶性动静脉畸形，包括大脑。 激活素受体样激酶(ALK1)的突变是2型高血压(HHT2)的原因，HHT2代表25- 占所有HHT病例的57%。Alk1是骨形态发生蛋白配体的I型转化生长因子β受体，其机制是 导致动静脉畸形的原因还知之甚少。基于我们强大的初步数据，我们建议建立一种新的 HHT2-BAVM小鼠模型，利用该模型识别对AVM发病至关重要的分子调控因子，使用 这既是有针对性的方法，也是无偏见的全基因组表达谱。为此，我们建议 建立急需的强大的临床前动物模型，忠实地模拟疾病的某些方面 HHT2患者的临床表现。现有的HHT小鼠模型在总结临床方面是有限的。 表现形式。使用尖端策略，我们开发了一个有用的HHT2-BAVM小鼠模型，通过 在脑内皮细胞中特异性地删除了这两个Alk1等位基因，并获得了强有力的初步数据 这种缺失会导致健壮的脑动静脉畸形、颅内出血和神经系统后果，而不是 身体其他部位可检测到的缺陷。我们将首先使用创新的、高性能的 分辨率双光子成像通过颅窗进入活体大脑中的血管系统，实现 5D透视(3D血管结构加上随时间变化的血流速度)。W候选人 促进脑动静脉畸形形成的分子调节因子包括房室编程、内皮屏障、 Alk1缺失小鼠的炎症、内皮细胞到间充质转化和超氧化物产生 脑血管内皮细胞。最后，我们将执行前沿的基因组表达谱来阐明Alk1 目标基因，然后使用生物信息学工具根据其功能对识别的基因进行分类 特点。我们提出的目标包括技术和概念创新的组合，将 提高对AVM形成和HHT发病机制的分子机制的认识。我们的 工作将为这些疾病建立一个强大的临床前模型，揭示新的分子机制 潜在的疾病病因，并影响未来的临床实践中的HHT和BAVM患者。 E也将进行调查