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). In addition we are leading large national and international studies to identify novel genetic drivers of PAH (www.ipahcohort.com) and chronic thromboembolic pulmonary hypertension.
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. Recently, we discovered that bone morphogenetic protein 9 (BMP9) can reverse and prevent pulmonary arterial hypertension in preclinical models by targeting the endothelial BMPR-II/ALK1 receptor complex, suggesting a promising new treatment for patients. This research has led to a university spin-out company, MORPHOGEN-IX (www.morphogen-ix.com), to take this new treatment into the clinic.
Nick Morrell is one of the founding board members of the Pulmonary Vascular Research Institute (PVRI), the only global medical research charity fighting pulmonary vascular disease (PVD). The PVRI’s vision is to reduce the global burden of PVD within the next two decades, through global collaboration, striving for excellence in clinical care, research and education in PVD (www.pvrinstitute.org).
We are defining the molecular recognition between bone morphogenetic protein family ligands and their receptors. The BMP9(10)/BMPR-II/ALK-1 complex is the focus of current studies. We use structure-based protein engineering to screen and generate potential biological therapeutics that enhance BMPR-II signalling specifically in the vasculature. We work with Prof. Morrell to validate the potential biological therapeutics in preclinical models and clinical trials for treating pulmonary arterial hypertension
Our lab is interested in understanding how cells acquire an identity, how this identity is maintained and how stable the identity is in the context of cardiovascular biology and disease and also in pluripotent/progenitor states. We do this by studying cellukar programming (differentiation) and reprogramming (using exogenous factors). As a disease focus we work on pulmonary arterial hypertension, in which vessels in the lung become obstructed because cells have altered identity and over-proliferate. This causes a back-pressure of blood flow in the right side of the heart, ultimately leading to heart failure. In PAH all the major cardiovascular lineages (cardiomyocytes, endothelial cells, pericytes and smooth muscle cells) are affected allowing us a useful model to study how these cells acquire identity and also how these cells interact with each other and with environmental factors such as inflammation and hypoxia.
At the beginning of this century two independent groups discovered mutations in the bone morphogenetic protein receptor type II (BMPR2) gene, a transforming growth factor beta (TGFß) cell surface receptor, which increase the risk of developing pulmonary arterial hypertension (PAH). Since then, additional disease-causing genetic variation has been identified in genes belonging to the TGFß/BMP-signalling pathways (i.e. ACVRL1 (ALK1), ENG, SMAD9) and more recently also in genes not directly associated with these molecular pathways (i.e. CAV1, KCNK3 (TASK1), EIF2AK4 (GCN2)). Our research ambition is to characterise the underlying genetic landscape of this rare disease to even greater detail by deploying current genomics, epigenomics and transcriptomics approaches.
The main focus of this group currently is the sequencing of more than a thousand whole genomes of adults and children diagnosed with PAH as part of the NIHR BioResource – Rare Diseases 10k whole genome sequencing (WGS) project. In order to get access to large numbers of patients with this rare condition all PAH specialist centres across the UK got together to form a national consortium, the National Cohort Study of Idiopathic and Heritable PAH, for patient enrolment, sample collection and in-depth phenotype capture. To investigate the genotype-phenotype relationship of both the protein-coding and non-coding fraction of the genome, the data integration and genome-wide association is enriched by additional functional multi-omics annotation derived from blood outgrowth endothelial cells (BOECs) in collaboration with the Blueprint Project and other consortium partners.
Our work also comprises the implementation of infrastructure solutions to support the necessary logistics of these large-scale projects as well as the development of new bioinformatics approaches to process and analyse the vast amount of data generated by these high-throughput screens, i.e. exploring big data solutions using the Hadoop framework. On these topics we are closely collaborating with the University of Cambridge High Performance Computing Service (HPCS).
These projects are funded by the National Institute for Health Research (NIHR), the British Heart Foundation (BHF) and the Medical Research Council (MRC).