Deficiency of bone morphogenetic protein type II receptor (BMPRII) signaling is causally implicated in the pathobiology of pulmonary arterial hypertension (PAH). Targeting of BMPRII signaling to improve the function of vascular endothelium could be desirable therapeutic intervention for PAH.
Heterozygous germline mutations of the BMP type II receptor are responsible for the majority of cases of heritable PAH and 15-40% idiopathic PAH. In this study we are aim to clarify the key target of BMPRII in pulmonary vasculature and apply into the drug screening. We identified that the Id (Inhibitor of DNA binding) family of basic-helix-loop helix proteins is a major transcriptional target of BMP signalling in human pulmonary artery smooth muscle cells (PASMCs) and is directly affected by mutations or deficiency of BMPR-II(QPCR). We are now employing genomic recombineering to generate a human Id1/3 promoter derived dual reporter in human embryonic stem cells derived vascular cells, and set up a platform with it to screen small molecules library to identify novel compounds for enhancing Id gene transcription in relevant cell types as potential therapies for PAH. Also we generated hESCs-R899X with CRISPR/Cas9 to demonstrate the effect of Heritable PAH (HPAH) bearing mutation on endothelial differentiation and tube formation. We demonstrated a BMP signaling up-regulator effectively rescued the expression of Apelin in heterozygous autologous cells by fluorescent immunostaining.
The combination of stem cell technology and cellular molecular mechanism of PAH enable the development of PAH targeted therapy.