Oestrogen and oestrogen metabolites in pulmonary arterial hypertension

Pulmonary Arterial Hypertension (PAH) is a disease where the blood vessels of the lungs thicken and close down. This puts strain on the right side of the heart which eventually fails. Survival is very poor and many more women than men get this disease. The sex hormone oestrogen (E2) can cause similar changes to the blood vessels and this may be due to them being broken down (metabolised) in the body to other more toxic chemicals. Many clinical trials are ongoing using drugs that interfere with the effects of E2. Using a novel assay we will measure E2 and its metabolites in the blood taken from patients with PAH and see how the change with disease severity, sex, age and obesity. We will also examine how the lungs themselves metabolise E2 in patients. We will analyse blood from patients in clinical trials for drugs that affect E2. We will to see how the drugs affect E2 and its metabolism and how this relates to the therapeutic effects of the drugs. We will examine lung blood vessel cells from patients with PAH and examine how E2 and its metabolites affect the way they grow and move. We will also study a rat model of PAH to determine how E2 metabolism changes during the development of the disease and is affected by the sex of the animal.

Pulmonary arterial hypertension (PAH) is a progressive disease that leads to right heart failure. The estimated survival rate at 3 years after diagnosis is only ~74% and the incidence of PAH is greater among women than men. Preclinical and clinical evidence suggest that manipulation of oestrogen (E2) synthesis, action and/or metabolism might offer a novel therapy for PAH. Indeed, four ongoing proof-of-concept clinical trials are investigating drugs that manipulate the synthesis and effects of E2. The principal investigators of these trials are collaborators in the current research proposal. It is unclear if the pathogenic effects of E2 are due to E2 itself or due to dysfunctional oestrogen metabolism leading to the accumulation of mitogenic metabolites that cause pulmonary vascular remodelling. The effects that novel drugs are having on E2 metabolism are also unclear. There are currently no blood-borne markers or non-invasive tests that can diagnose PAH. It is therefore important to investigate if unique blood-borne E2 metabolites are markers of the disease. We will examine E2 metabolism in plasma from patients. Preclinical and molecular studies in human pulmonary arterial smooth muscle cells from patients will further define the mechanisms behind the effects of E2 metabolites. We will apply a unique LC-MS/MS assay to determine the levels of E2 and its metabolites in the plasma from patients and stratify these with sex, BMI, disease status and severity. This will also be determined in patients registered into three clinical trials of drugs that affect E2 synthesis or E2 receptor function. We will determine transpulmonary gradients of plasma E2 and its metabolites in patients with PAH. Patients are very heterogeneous in age, environment, severity of disease, ongoing medication and responsiveness to drugs; therefore a reproducible animal model will allow controlled examination of the effects of sex, development of disease and novel therapies on E2 metabolism.

During the course of this study we will seek to attract R&D investment and commercial partners to drive any novel therapeutic strategy that this research uncovers into the clinic. For example we will approach United Therapeutics, GSK, Altavant and Janssen as all have an interest in pulmonary arterial hypertension. Professor MacLean has previous or ongoing collaborations with these companies. Morrell, Kawut, Austin and Ventetuolo are leading clinicians in this field and well placed to engage their contacts in pharmaceutical companies. Any novel target or marker discovered will be of extreme interest to these companies as will be transferable to other lung diseases. Well beyond this study, this could lead ultimately to improvement to diagnosis, the quality of life and survival of PAH patients.

In vivo techniques are recognised by the MRC and BBSRC as vulnerable skills. Professor MacLean is recognised as an expert in the training of scientists in in vivo skills, having run one of the four UK Integrative Mammalian Biology centres (co-funded by the MRC) and secured over £4M of postgraduate training grants for in vivo. This research will assist in retaining these skills within the academic sector by delivering highly skilled researchers in in vivo skills. This will apply to the postdoctoral research assistant (PDRA) and also more junior researchers who will be trained up in these skills by the PDRA.

PDRA development and mentoring is taken seriously and they will be given the opportunity to supervise and train undergraduates and postgraduates. Mentoring will ensure that the PDRAs research productivity is not compromised by this. MacLean is an experienced mentor, currently being a mentor for the Academy of Medical Sciences SUSTAIN programme. It is possible that after the research is finished the PDRA could transfer these skills to the commercial sector which has acknowledged the continued requirement for researchers trained in these skills.

Professor MacLean received an MBE for her many Public Engagement (PE) activities. She is involved in The University PE strategy and has run Glasgow's Cafe Scientifique every month since 2004. These events have informed and will continue to inform the public about research and the value of research including the use of animals. This contributes to a cultural change to the UKs understanding and tolerance of such research. This will be facilitated by the Pathways to Impact activities associated with this research.

The research will be of great interest to the Pulmonary Hypertension Associations led by patient groups who keep patients informed of new promising therapies and MacLean will maintain a dialogue with these societies.
Through her Pathways to Impact activities, MacLean will engage with and inform a local MP, Scientific Advisor for Chief Scientists Office, Head of Research and Enterprise, Director of Scottish Enterprise, representative from Research Councils, Charities, Scottish Development International and representatives from the NHS. In addition, basic scientists and other clinicians in the field of PAH have already expressed an interest in the work leading up to this proposal and will gain important knowledge and understanding about the potential of such a novel therapeutic strategies.