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Oestrogen metabolism and metabolomics in pulmonary hypertension


Project Description

Pulmonary Arterial Hypertension (PAH) is a disease that affects more women than men. The project will examine blood levels of oestrogen and its metabolites in PAH patients as well as conducting metabolomics screens, in vivo, in vitro and functional assays.

Pulmonary Arterial Hypertension (PAH) affects up to 4-fold more women than men, suggesting that aberrant oestrogen (E2) signalling may be causative. The project will examine blood levels of oestrogen and its metabolites from males and females, controls and patients with iPAH and hPAH. The effects of these metabolites on pulmonary vascular function, the development of experimental PAH and on proliferation of human pulmonary arterial smooth muscle cells (PASMCs) will be determined.
Hypothesis: Dysfunctional E2 metabolism in PAH increases damaging proliferative E2 metabolites within lung, contributing to the pathobiology of PAH.

The student will examine the actions of E2 metabolites on pulmonary arterial smooth muscle and endothelial cells from controls and PAH patients. Their effects on proliferation (cell counting) and cell migration (scratch assay/confocal microscopy) will be determined. Alterations caused by E2 and its metabolites on BMPR2 signalling and other pro-proliferative pathways will also be assessed (immunohistochemistry, western blotting, RT-PCR, pharmacological intervention using selective antagonists against pro-proliferative pathways).
The effects of these metabolites on pulmonary arterial contractility will also be assessed using wire myography.
The ability of metabolites to influence development of PAH will be determined in a model of PAH. The effects of inhibiting E2 metabolising enzymes such as CYP1B1 and CYP1A1, involved in the development of PAH, will be determined.

The student will be trained in immunohistochemistry, western blotting, RT-PCR, wire myography, cell counting, scratch assay/confocal microscopy, breeding mice, in vivo haemodynamics, drug administration, in vivo pharmacology, metabolomics and big data analysis. These are all valuable skills which will ensure a competitive CV when the student enters the competitive postdoctoral/industrial stage of their careers. The in vivo skills are an important addition as these are in great demand in scientific research. The student will complete other transferable skills workshops and training via the Researcher Development Programme (equivalent to at least 60 credits) and these will align with the four RDP domains in discussion with the supervisor and use of the tools provided. For example these will be selected at appropriate times during the PhD and could include grant writing, career development, entrepreneurship, communication skills and public engagement (PE). MacLean has a keen interest in PE and through her roles as VP of the Royal Society of Edinburgh, regional ambassador for the Acad. Med. Sci. and running Glasgow’s Café Scientifique she will identify PE opportunities for the student.

Funding Notes

This project is funded by the University of Strathclyde.

Applicants should submit a copy of their CV to Professor Mandy MacLean ()
Applicants can also apply online using the following link View Website

References

MAIR KM, HARVEY KY, HENRY AD, HILLYARD DZ, NILSEN M, MACLEAN MR. Obesity Alters Oestrogen Metabolism and Contributes to Pulmonary Arterial Hypertension. Eur Respir J. 2019 Mar 28. doi: 10.1183/13993003.01524-2018. [Epub ahead of print]
DOCHERTY CK, NILSEN M, MACLEAN MR. Influence of 2-Methoxyestradiol and Sex on Hypoxia-Induced Pulmonary Hypertension and Hypoxia-Inducible Factor-1-α. J Am Heart Assoc. 2019 Mar 5;8(5):e011628.
DENVER N, KHAN S, STASINOPOULOS I, CHURCH C, HOMER NZ, MACLEAN MR, ANDREW R. Derivatization enhances analysis of estrogens and their bioactive metabolites in human plasma by liquid chromatography tandem mass spectrometry. Anal Chim Acta. 2019 Apr 25;1054:84-94.
DEAN A, GREGORC T*, DOCHERTY CK, HARVEY KY, NILSEN M, MORRELL NW, MACLEAN MR (2017). Role of the aryl hydrocarbon receptor in Sugen 5416-induced experimental pulmonary hypertension. Am Journal Resp Cell Mol Biol. In Press *Joint first authors
HOOD KY, MONTEZANO AC, HARVEY AP, NILSEN M, MACLEAN MR, TOUYZ RM. (2016).
Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Mediated Redox Signaling and Vascular Remodeling by 16α-Hydroxyestrone in Human Pulmonary Artery Cells: Implications in Pulmonary Arterial Hypertension. Hypertension, Sep; 68(3):796-808.
DEAN A, NILSEN M, LOUGHLIN L, SALT IP, MACLEAN MR (2016). Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition. Hypertension, Aug; 68(2):446-54.
MAIR KM, YANG XD, LONG L, WHITE K, WALLACE E, EWART MA, DOCHERTY CK, MORRELL NW, MACLEAN MR. Sex Affects BMPR-II Signalling in Pulmonary Artery Smooth Muscle Cells. Am J Respir Crit Care Med. 2015 191(6):693-703.
MAIR KM, WRIGHT AF, DUGGAN N, ROWLANDS DJ, HUSSEY MJ, ROBERTS S, FULLERTON J, NILSEN M, LOUGHLIN L, THOMAS M, MACLEAN MR (2014). Sex-dependent influence of endogenous estrogen in pulmonary hypertension. Am J Respir Crit Care Med. 15;190(4):456-467.

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