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MRC DiMeN Doctoral Training Partnership: Developing novel therapies for babies born with univentricular hearts


Project Description

Outstanding graduate scientists are invited to apply for a PhD Studentship to study the molecular mechanisms that cause detrimental pulmonary vascular remodelling in babies born with univentricular hearts, and to develop treatments that will prevent this problem and protect the infant lungs through childhood. Because a univentricular heart cannot separate the pulmonary blood from the systemic circulation, these babies undergo surgery to supply the lung with blood from the superior vena cava (SVC). However, this altered circulation causes the lung vasculature to develop arteriovenous (AV) connections that prevent efficient blood oxygenation and cause severe hypoxia. Preclinical studies have established that abnormal AV connections develop in the absence of ligands BMP9&10. Furthermore, as BMP9&10 (released into blood by liver and right atrium, respectively) are severely reduced in blood derived from the SVC, we reason that reduced BMP9/10 signalling in pulmonary endothelial cells explains the development of AV malformations in the lungs of these children. Importantly, restoration of BMP9/10 to the lung circulation provides an important therapeutic opportunity that will be tested as part of this project. The student will have access to patient blood samples to examine changes in circulating factors; will use preclinical models of the altered pulmonary circulation to investigate the stages involved in vascular remodelling and to test therapeutic interventions; and will use cell culture to determine the BMP signalling changes that occur during the detrimental vascular remodelling and its rescue with therapeutic forms of BMP. Successful completion of this project will yield increased understanding of why lung AV malformations occur in these infants and will identify novel therapeutics that can be taken forward towards clinical validation to prevent this devastating disease. Students will be encouraged to present their findings at national and international conferences and to publish in high-quality, international journals.

The PhD student will be jointly supervised by Professor Helen Arthur (Newcastle University) and Dr Allan Lawrie (University of Sheffield).

Professor Helen Arthur’s group has a long standing interest in how TGFbeta and BMP signalling regulates vascular development and maturation. She has established a number of preclinical models that she has used to determine how key BMP receptors function in vascular endothelial cells to maintain a normal healthy vasculature and have been used to develop and test new therapeutic interventions. These models have been shared across many other laboratories leading to numerous ongoing national and international collaborations. More information on Professor Arthur’s work can be found here: http://www.ncl.ac.uk/igm/staff/profile/helenarthur

Dr Allan Lawrie’s laboratory has a strong interest in understanding the molecular mechanisms that underlie the maintenance of a healthy lung vasculature with particular focus on pulmonary arterial hypertension. He has a strong translational and collaborative focus working with the Sheffield Pulmonary Vascular Disease Unit, with all UK national Pulmonary Arterial Hypertension Centres, and multiple international collaborations. His research encompasses a combination of clinical, preclinical and molecular studies. More information can be found here: https://www.sheffield.ac.uk/iicd/profiles/lawrie

Entry Requirements:
Applicants should possess a good honours degree or equivalent in Biological/Medical Sciences, molecular biology, or a related discipline.
Enquiries: For an informal discussion about this studentship please contact Prof Helen Arthur:
Email:
Tel: +44 (0) 191 241 8648

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck!

References

S Tual-Chalot, P Oh and HM Arthur Mouse Models of Hereditary Haemorrhagic Telangiectasia: Recent Advances and Future Challenges (2015) Frontiers in Genetics 6:25.

Thompson AAR & Lawrie A (2017) Targeting Vascular Remodeling to Treat Pulmonary Arterial Hypertension. Trends in Molecular Medicine, 23(1), 31-45.

Y Jin, L Muhl, M Burmakin, Y Wang, C Betsholtz, HM Arthur and L Jakobsson. (2017) Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling. Nature Cell Biol 19 (6), 639-652.

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