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

项目摘要/摘要动静脉（AV）畸形（AVM）是血管异常，可直接从动脉分流到A 静脉，引起器官功能障碍。 AVM发病机理知之甚少，限制了合理设计分子干预。我们的长期目标是为AVM开发更好的治疗性治疗治疗方案有限且风险。我们的策略是专注于大脑AVM（BAVM），因为它们是最大的危险的AVM和BAVM中的发现适用于体内其他地方的AVM。大多数Bavms是零星的，但遗传性bavms，例如在院里出血性毛细血管扩张（HHT）中看到的研究疾病过程的分子机制的绝佳机会。 HHT是常染色体主要的遗传疾病，其特征是包括大脑在内的全身多灶性AVM。激活素受体样激酶（ALK1）中的突变负责2型HHT（HHT2），代表25-- 所有HHT病例中有57％。 ALK1是BMP配体的I型TGFβ受体，也是ALK1的机制导致AVM的理解很少。在我们强大的初步数据的基础上，我们建议建立一个小说 HHT2-BAVM小鼠模型，使用该模型鉴定出使用AVM发病机理至关重要的分子调节剂靶向方法和无偏基因组的表达分析。为此，我们建议建立急需的健壮临床前动物模型，忠实地模拟疾病的某些方面 HHT2患者的演讲。现有的HHT鼠标模型受到概括临床的限制表现。使用尖端策略，我们开发了一个有用的HHT2-BAVM的鼠标模型在脑内皮细胞中删除两个ALK1等位基因，并获得了强大的初步数据这种缺失会导致强大的BAVM，颅内出血和神经系统后果，而没有可检测到体内其他地方的缺陷。我们将首先使用创新，高级的模型充分表征该模型通过颅骨窗户进行两光量成像，以获取活体大脑中的脉管系统，实现了 5D透视（3D血管结构加上随时间的血液速度）。 W候选人促进BAVM形成的分子调节剂，包括AV编程，内皮屏障， ALK1缺失的小鼠炎症，内皮到间质转变和超氧化物产生大脑原子座。最后，我们将进行尖端的基因组表达分析以阐明ALK1 靶基因，然后使用生物信息学工具根据其功能识别基因的类别特征。我们提出的目标包括技术和概念创新的结合促进对AVM形成和HHT发病机理的分子机制的了解。我们的工作将为这些疾病建立强大的临床前模型，发现新的分子机制疾病病因的基础，并影响HHT和BAVM患者的未来临床实践。 E也将调查