Pulmonary Vascular Research
Lab Head: Dr Allan Lawrie
The main focus of the research conducted within the pulmonary vascular research group laboratory aims to improve our understanding of the molecular mechanism underlying the pathogenesis of pulmonary arterial hypertension (PAH). We have a strong focus on bi-directional translation, utilising patient samples to aid novel target discovery, and the subsequent development of novel therapeutics targeting these.
We also have a strong interest in biomarkers and through collaboration with clinical colleagues in the Sheffield pulmonary vascular disease unit (SPVDU) have developed a growing biobank of blood products (DNA/RNA/Plasma/Serum) from patients with all major forms of adult pulmonary hypertension. In addition, we collaborate both nationally (Morrell, Cambridge & Wilkins, Imperial College) and internationally (McLoughlin, Dublin & Zamanian/Rabinovitch, Stanford) with colleagues to share this resource and pursue joint projects of mutual interest.
We are actively involved in a new MRC and BHF funded study to generate a national cohort of patients with Idiopathic and heritable PAH (IPAH/HPAH), and family members of those with heritable PAH.
More information about PAH can be found on the Pulmonary Hypertension Association UK website.
Pathologically, PAH is characterised by sustained vasoconstriction and a progressive obliteration of small resistance pulmonary arteries and arterioles through a process of medial thickening, intimal fibrosis and the formation of angioproliferative (plexiform) lesions. Endothelial dysfunction and pulmonary artery endothelial cell (PA-EC) apoptosis/dysfunction are thought to play an important early role in disease pathogenesis. Subsequent proliferation and migration of medial cells including smooth muscle cells (PA-SMC), fibroblasts and PA-EC drives the pulmonary vascular remodelling.
The last 10-15 years have seen some major breakthroughs in our understanding of the pathobiology of PAH. There are now well-established mechanistic insights into disease pathogenesis, for example, bone morphogenetic protein receptor type II (BMP-RII) mutations, the involvement of serotonin pathway, inflammation, mitochondria metabolism and many others. Despite these important insights, the precise cell and molecular mechanisms leading to disease manifestation, and driving pathogenesis remain poorly understood.
OPG/TRAIL Axis in PAH
Osteoprotegerin (OPG, TNFRSF11B) is expressed and secreted from cells within the heart, lung, vascular and immune system. OPG competes with Receptor Activator of Nuclear Factor-κB (RANK, TNFRSF11A) for the binding of RANK ligand (RANKL, TNFSF11) to regulate osteoclast differentiation and activation. OPG also has anti-apoptotic action through interaction with TNF-related apoptosis-inducing ligand (TRAIL, TNFSF10). TRAIL is a type II transmembrane protein and its extracellular domain can be proteolytically cleaved from the cell surface to act as a soluble cytokine capable of binding to 5 TRAIL receptors; 2 death receptors DR4/5 (TRAIL-R1/TRAIL-R2), 2 membrane bound decoy receptors DcR3/4 (TRAIL-R3/TRAIL-R4) and OPG.
We have previously demonstrated that OPG and TRAIL are abundantly expressed in remodelled pulmonary arteries from patients with IPAH. Critically, both OPG and TRAIL are up-regulated by several of the previously described pathways, that OPG and TRAIL are potent stimuli for proliferation and migration of PA-SMC, and that serum levels of OPG are elevated in IPAH, and predict outcome in patients with IPAH.
Recent data has also demonstrated that antibody blockade of TRAIL can reverse PAH in established disease models.
Our current research can be broadly be divided into the following themes:
- Mechanism of OPG-induced proliferation of PA-SMC and PA-EC.
- Novel protein binding partners within the OPG/TRAIL axis.
- Cellular source of TRAIL and OPG and responding cells.
- OPG and TRAIL in right ventricular remodelling.
- Development of novel therapeutic antibodies.
- Clinical relevance of SNPs in the OPG/TRAIL axis for prognosis.
Current Research Projects
1. Investigation into the role of osteoprotegerin in pulmonary arterial hypertension. Medical Research Council - Career Development Award 9/2008-10/2013.
It remains unclear whether OPG is causal and/or a potential new biomarker in PAH. We are currently determining the temporal relationship between the pattern of OPG expression and onset/progression of PAH. We are also focused on identifying associated binding partners and signalling cascades involved in OPG-induced PA-SMC proliferation and migration. The aim of these studies is to identify molecules that can be treated to block this pathway, and potentially identify a new targets for therapy.
2. Investigation into OPG and related biomarkers in incident cases of pulmonary hypertension. British Heart Foundation Project Grant 4/2012-3/2015.
We have recently demonstrated that serum levels of OPG can predict survival in patients with IPAH. The aim of this study is to determine whether OPG and associated proteins correlate with clinical status and survival, and compare them with biomarkers reflecting heart failure. The utility of these biomarkers as a prognostic indicator and diagnostic tool in pulmonary vascular disease will subsequently be explored.
3. Developing antibody therapies targeting the OPG/TRAIL axis for the treatments of pulmonary hypertension. Medical Research Council (Confidence in Concepts) 2013.
Through a commercial partnership with a new University of Sheffield spin-out, PH Therapeutics Ltd we are currently exploring the potential to develop novel therapeutic antibody therapies for clinical translation.
4. Investigation into microRNAs in human and experimental models of pulmonary arterial hypertension. Medical Research Council (Clinical Research Training Fellowship to Dr Alex Rothman) 12/2012-11/2015.
Through an extensive screen of our patient biobank we have recently identified several microRNAs of interest. We are currently int he process of validating these in additional patient samples, and determining their phenotypic consequence in experimental models of PAH.