Endothelial bone morphogenetic protein (BMP) signaling underlies several serious cardiovascular conditions including pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia. BMP9 and BMP10 are the specific ligands that activate this pathway, and BMP9 has been shown to reverse PAH in multiple preclinical models.
My group are interested in the molecular recognition events that regulate BMP9 and BMP10 signaling, and how to manipulate such protein-protein interactions to facilitate the translation of BMP9-based therapy into clinic. We use a range of techniques including structural biology, biophysics, molecular biology, biochemistry as well as signaling and functional assays in primary endothelial cells. Through our structural-based design, we have generated a mutant library of BMP9. Screening of this library has produced promising BMP9 variants that are being further developed at a university spin-out company, Morphogen-IX (www.morphogen-ix.com).
Ormiston ML, Upton PD, Li W, Morrell NW. (2015) The promise of recombinant BMP ligands and other approaches targeting BMPR-II in the treatment of pulmonary arterial hypertension. Glob Cardiol Sci Pract 4:47.
Jiang H, Salmon RM, Upton PD, Wei Z, Lawera A, Davenport AP, Morrell NW, Li W. (2016) The Prodomain-bound Form of Bone Morphogenetic Protein 10 Is Biologically Active on Endothelial Cells. J Biol Chem. 291:2954-66.
Wooderchak-Donahue WL, McDonald J, O'Fallon B, Upton PD, Li W, Roman BL, Young S, Plant P, Fülöp GT, Langa C, Morrell NW, Botella LM, Bernabeu C, Stevenson DA, Runo JR, Bayrak-Toydemir P. (2013) BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia Am J Hum Genet. 93:530-7.
Li W, Johnson, DJD, Esmon, CT, Huntington, JA (2004) Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin. Nature Structural & Molecular Biology. 11, 857-62.