Molecular Pathogenesis of Hereditary Hemorrhagic Telangiectasia

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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