Dr. Yu’s laboratory has been focused on determining how signaling via the bone morphogenetic protein (BMP) signaling pathway contributes to vascular disease, and how BMP signals regulate the remodeling and function of mesenchyme-derived tissues. First, we have examined models of disease thought to entail gain-of-function in the BMP signaling pathway. These include vascular and valvular calcification, and ectopic ossification of skeletal muscle and connective tissues, which we have studied in small animals using models of atherosclerosis and fibrodysplasia ossificans progressiva (FOP). These diseases represent a spectrum of heterotopic ossification (HO) disorders. We are interested in (i) the mechanisms by which BMP signals may synergize with other inflammatory or osteogenic stimuli in order to induce a program of endochondral bone formation in soft tissues in these diseases, and (ii) the progenitor populations which are recruited in order to form endochondral tissues. Second, we have studied a disease thought to entail loss-of-function in the BMP signaling pathway, idiopathic pulmonary arterial hypertension (IPAH). Loss-of-function mutations in the gene encoding the BMP type II receptor (BMPR2) have been detected in the majority of individuals with familial IPAH, and in a proportion of individuals with sporadic IPAH. We have modeled this disease with conditional BMPR2 knock-out mice, examining their pulmonary vascular function in vivo and their tissues in vitro for evidence of aberrant BMP-mediated functions in a broad sense. In addition, we have probed the circulation of individuals with IPAH and other forms of PAH for altered regulation of molecules which regulate BMP signaling and endothelial homeostasis as potential biomarkers of PAH. Third, we are refining and producing novel pharmacologic tools for probing the BMP signaling pathway. In collaboration with Charles Hong and Randy Peterson, we identified dorsomorphin, the first small molecule shown to selectively antagonize BMP type I receptor kinase activity (vs. Activin and TGF-β receptors). This effort has yielded pharmacophores based on dorsomorphin as well as novel scaffolds, which are being refined for enhanced selectivity within the BMP signaling pathway. These molecules have gained widespread use as research tools, and hold promise as potential therapies for BMP signaling gain-of-function diseases.