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

基本信息

批准号：
10339385
负责人：
Rong Wang
金额：
$ 47.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/10339385
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 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 dysfunction brain endothelial cell clinical practice density drug candidate genetic association genome-wide innovation malformation mouse model neurobehavioral new therapeutic target novel novel therapeutic intervention postnatal pre-clinical rational design ribosome profiling success therapeutic candidate transcriptome two-photon

项目摘要

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

项目概要/摘要动静脉 (AV) 畸形 (AVM) 是一种将血液从动脉直接分流至静脉的血管异常。静脉，引起器官功能障碍的发病机制尚不清楚，限制了合理设计。我们的长期目标是开发更好的 AVM 治疗方法，就像目前一样。我们的策略是关注脑动静脉畸形（BAVM），因为它们是最危险的。危险的 AVM，BAVM 中的发现也适用于身体其他部位的 AVM。散发性但遗传性的 BAVM，例如遗传性出血性毛细血管扩张症 (HHT) 中所见的 BAVM，可提供一种 HHT 是一种常染色体，是研究疾病过程分子机制的绝佳机会。显性遗传性疾病，其特征是全身（包括大脑）多灶性 AVM。激活素受体样激酶 (ALK1) 的突变导致 2 型 HHT (HHT2)，它代表 25- 57% 的 HHT 病例中 Alk1 是 BMP 配体的 I 型 TGFβ 受体，以及 Alk1 的机制。导致 AVM 的原因尚不清楚。基于我们强有力的初步数据，我们建议建立一种新颖的方法。 HHT2-BAVM 小鼠模型，利用该模型来识别对 AVM 发病机制至关重要的分子调节因子，使用为此，我们建议采用有针对性的方法和公正的全基因组表达谱。建立急需的稳健的临床前动物模型，忠实地模拟疾病的某些方面 HHT2 患者的现有小鼠模型在重现临床方面受到限制。使用尖端策略，我们开发了一种有用的 HHT2-BAVM 小鼠模型。专门删除脑内皮细胞中的两个 Alk1 等位基因，并获得了强有力的初步数据这种缺失会导致严重的 BAVM、颅内出血和神经系统后果，而无需我们将首先使用创新的、高水平的方法来充分描述该模型的特征。通过颅窗进行分辨率双光子成像以访问活体大脑中的脉管系统，从而实现 5D 透视（3D 血管结构加上随时间变化的血流速度 W 候选）。促进 BAVM 形成的分子调节因子，包括 AV 编程、内皮屏障、 Alk1 缺失小鼠的炎症、内皮间质转化和超氧化物产生最后，我们将进行尖端的基因组表达谱分析来阐明 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我们提出的目标包括技术和概念创新的结合。我们对 AVM 形成和 HHT 发病机制的分子机制的了解。工作将为这些疾病建立强大的临床前模型，揭示新的分子机制揭示疾病病因，并影响 HHT 和 BAVM 患者未来的临床实践。 e还将调查