Research

The Morrell laboratory is studying the molecular mechanisms underlying pulmonary arterial hypertension. In particular our research is focussed on how mutations in the bone morphogenetic protein type II receptor (BMPR-II), a receptor member of the transforming growth factor-beta superfamily, cause familial pulmonary arterial hypertension (PAH).

Our research is revealing how BMPR-II mutation leads to dysfunctional signalling, gene transcription and vascular cell biology. This work has also revealed a broader role for BMPR-II in angiogenesis, inflammation, iron metabolism and innate immunity.

Our research has suggested new approaches to the rescue of BMPR-II deficiency. These include gene therapy, enhanced BMPR-II transcription and the demonstration that BMPR-II is rapidly degraded by the lysosome. Inhibition of the lysosomal turnover of BMPR-II with agents such as chloroquine increase cell surface BMPR-II and are effective in experimental models of pulmonary hypertension. Loss of BMPR-II is associated with increased activity of other important growth factor pathways including platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) signalling. We have confirmed that inhibitors of these pathways are effective in experimental models of PAH, and PDGF inhibition has now proven beneficial in patients with PAH.

Read more