Molecular mechanisms underlying Arteriovenous Malformations associated with HHT

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PROJECT SUMMARY Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disease that affects males and females from all racial and ethnic groups, and is found in ~1 in every 5000 people. HHT is characterized by inappropriate connections between arteries and veins, called arteriovenous malformations (AVMs). These fragile connections can bleed and rupture leading to anemia, aneurysms, stroke and even death. Remarkably, there are currently no drugs for effective treatment of AVMs in HHT patients, despite the previous identification of the defective signaling pathway associated with HHT. Genetic causes of HHT are linked to the Transforming Growth Factor-β (TGFβ) signaling pathway, with approximately 85% of patients showing mutations in the Endoglin (Eng) or Activin receptor-like kinase 1 (Acvrl1) co-receptors. About 4% have defects in the downstream transcription factor, Smad-related protein 4 (Smad4). Despite many years of HHT research mainly focused on Eng and Acvrl1, two crucial gaps in our knowledge remain - a comprehensive understanding of the cell morphological and biological defects of the HHT vasculature, and identification of the downstream genes that are mechanistically responsible for the vascular defects. We have created a novel mouse model of AVM/HHT whereby genetic ablation of Smad4 specifically in blood vessels effectively replicates the cell biological defects associated with HHT. Using our model we have begun a detailed molecular and cellular characterization of HHT vessels in vivo, and initial RNA-seq and ChIP-seq experiments have identified potential novel regulators of AVM/HHT, including the vascular signaling proteins Tek and Angiopoietin 2 (Ang2), and the transcriptional co-factor Zmiz1. The central objective of this application is to answer two fundamental questions: What are the molecular and cellular mechanisms driving AVM/HHT pathogenesis and what are the downstream effectors of the TGFβ pathway that promote AVM/HHT? We will address these topics by testing our hypothesis that Smad4 transcriptionally controls downstream pathway components that are mechanistically responsible for AVM formation, via the following specific aims: 1) Identify the molecular and cellular events causing AVM formation and the Smad4 downstream effectors associated with AVM/HHT; 2) Examine the role of Tek/Angiopoietin signaling in generation and resolution of AVMs; and 3) Examine the role of Zmiz1 in AVM pathogenesis. Results obtained from these studies will advance our understanding of the mechanistic mediators of AVM pathogenesis and uncover new drug targets designed to treat the disease mechanisms of HHT.