Reversibility of adverse cardiac and electrophysiological remodelling with inhibition of hypoxia inducible factor in models of pulmonary arterial hypertension
The BHF 4-year MRes/PhD studentships at ICTEM typically comprise a 1-year MRes in Biomedical Research, followed by a 3-year PhD. During the MRes year, students undertake two laboratory projects which will prepare them for the PhD. This highly inter-disciplinary project, which combines cardiac electrophysiology and pulmonary vascular biology, will investigate the reversibility of adverse cardiac and electrophysiological remodelling with inhibition of hypoxia inducible factor in models of pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a debilitating and often fatal disease affecting both adults and children. The primary cause of death in PAH is right heart failure and accounts for approximately half of all PAH deaths. Sudden cardiac death, in large part due to ventricular arrhythmias, is the second commonest cause of death, responsible for 25% of the mortality in this group.
The significantly pressure-/volume-overloaded right ventricle (RV) undergoes a number of pro-arrhythmic changes at the cellular and tissue level, which are in part due to stretch.
There is currently no specific treatment available to limit and reverse the pro-arrhythmic changes due to PAH, and only very limited data exist to suggest that treatment with conventional PAH medications may attenuate and reverse some of the electrophysiological changes described above.
Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia, and their discovery led to the award of the Nobel Prize for Physiology/Medicine in 2019. Recently, the aberrant expression of HIF-2α in pulmonary vascular lesions has been associated with PAH disease severity. We reported that inhibition of HIF-2α activity significantly reduced pulmonary vascular haemodynamic and remodelling associated with severe disease and propose to investigate if HIFα inhibition is also associated with reversal of the adverse electrophysiological remodelling.
The PhD will have the following 3 aims:
1. To investigate the effect of HIFα inhibition on RV mechanical function in PAH
2. To investigate the effect of HIFα inhibition on right atrial (RA) and RV electrophysiology and arrhythmia susceptibility
3. To determine the impact of acute and chronic HIFα inhibition on RA and RV gene profiles in PAH using RNA-Seq studies.
The successful candidate will be based at the Ng and Cowburn labs at the Hammersmith Campus for the period of their study. They will also join a cohort of PhD students affiliated with the BHF Centres at Imperial, with particular interests in regenerative medicine and novel technologies. They will also link to the wider Imperial College through activities such as the Imperial Stem Cell and Regenerative Medicine Network.
To apply, you will need to complete the following two steps:
1) Please email Veena Dhulipala ([Email Address Removed]) with the following documents.
- Your CV
- The names and addresses of at least two academic referees
- A personal statement of no more than 1,000 words explaining your interest in the project
2) Please complete the Imperial College London’s online application site (https://imperialuk.elluciancrmrecruit.com/Apply/Account/Login).
Please note that you will have to complete both steps for your application to be considered. Please assume that your application has not been successful if you have not heard from us within a month of the closing date.
Closing date for all applications: 23.59 on Sunday 19th January 2020
Interviews will be held in early February 2020
Applicants must hold, or expect to obtain, a first or upper second-class honours degree or equivalent in an appropriate subject from a recognised academic institution. Candidates must fulfill College admissions criteria and meet BHF residency requirements. This is a highly interdisciplinary project and previous experience in at least one of the areas of study (cardiac electrophysiology, pulmonary vascular biology) is essential. Experience of ex vivo Langendorff heart perfusion and surgical techniques are desirable.
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