BMP10 IN CARDIOVASCULAR DEVELOPMENT AND HEREDITARY HEMORRHAGIC TELANGIECTASIA

项目总结

PROJECT SUMMARY Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder, afflicting approximately 1 in 5,000 people, that is characterized by development of arteriovenous malformations (AVMs). These fragile, direct connections between arteries and veins can lead to hemorrhage, anemia, brain abscess, or stroke. For lung, brain, and nasal lesions, the primary treatment options are invasive procedures that ablate, resect, or block flow through the AVM. Liver AVMs cannot be safely treated and severe liver involvement, which can lead to high-output heart failure, requires liver transplantation. Current medical therapies for HHT block angiogenesis or enhance clotting but do not target disease mechanism. As such, the goal of our research program is to understand disease mechanism to seed development of targeted medical therapies for HHT patients. HHT is caused by haploinsufficiency of one of three genes involved in endothelial cell bone morphogenetic protein (BMP) signaling: activin receptor-like kinase 1 (ACVRL1, or ALK1), endoglin (ENG), and SMAD4. Because signaling is approximately 50% of normal, one approach to therapy is to enhance pathway activation. The highly related BMP9 and BMP10 proteins, produced by the liver and heart, respectively, have been biochemically identified as high affinity ligands for both ALK1 and ENG, and both proteins are detected in serum. To address the requirements for BMP9 and BMP10 as ALK1 ligands in vivo, we generated zebrafish mutants. We found that bmp9 is dispensable, whereas the two zebrafish bmp10 paralogs, bmp10 and bmp10-like, are redundant with respect to embryonic AVM prevention and cardiac trabeculation, but have subfunctionalized to govern post-embryonic vessel maintenance (bmp10) and ventricular chamber growth (bmp10-like). In Aim 1, we will characterize vascular and heart defects in juvenile- to-adult zebrafish bmp10 mutants. We hypothesize that these mutants develop high output heart failure secondary to vascular defects, recapitulating disease progression in HHT patients and implicating BMP10 as the critical HHT ligand throughout life. In Aim 2, we will explore the cellular and molecular basis of heart defects in bmp10l mutant embryos, focusing on development after the linear heart tube stage. In Aim 3, we will use zebrafish, cell culture, and biochemistry approaches to dissect the physiological and biochemical basis for the specific requirement for BMP10 in post-embryonic vessel maintenance. These studies highlight BMP10 as a novel factor in the coordinate regulation of heart and vessel development and maintenance; implicate BMP10 as the relevant protein for ligand-based HHT therapy; and provide an invaluable new model for understanding the mechanistic relationship between AVMs and high-output heart failure.