Professor Nick Morrell

Genetics, epidemiology and cell biology of pulmonary hypertension

We study the molecular mechanisms underlying pulmonary arterial hypertension (PAH). In particular, our research focuses 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 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.

Using structural biology approaches (Dr Wei Li) we are defining the molecular interaction between bone morphogenetic protein ligands and receptors. The BMP9/BMPR-II/ALK-1 complex is the focus of these studies. The aim is to develop designer peptides or small molecules that enhance BMPR-II signalling specifically in the vasculature.

We are using induced pluripotent stem cells derived from patients with gain and loss of function in BMP pathways (Dr Amer Rana) to understand the impact of BMPs on heart and blood vessel development and function.

Our research is demonstrating the broader role of the BMP pathway in vascular disease and providing new insights into the pathogenesis of other conditions, including atherosclerosis.

National Pulmonary Hypertension Service

Our group has close links with the National Pulmonary Hypertension Service at Papworth Hospital, where Professor Morrell is the Research Director. We are employing next generation sequencing in our cohort of patients to define the genetic architecture of PAH, which may reveal further tractable targets for therapy. Our clinical research team has identified novel biomarkers for predicting survival in PAH patients and we are assessing better ways to measure response to therapy in patients using imaging techniques (MRI/CT) and physiological measurements of exercise and gas exchange. We have an active translational research programme at Papworth where new targets identified from basic science studies can be trialed for the first time in patients with severe PAH.