MRes/PhD studentships 20/21

Reversibility of adverse cardiac remodelling

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 project 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.

Contribution of liver endothelial cell gene

The project will investigate how genetic and/or epigenomic mechanisms of liver sinusoidal endothelial cells (LSEC) contribute to cardiometabolic diseases, such as non-alcoholic fatty liver disease and cardiovascular disease. To this end, the student will develop new in vitro systems to study LSECs and characterise them using state-of-the-art chromatin assays, including ATAC-seq and Cut&Tag. These new tools will be used to address fundamental questions related to the role of LSECs in cardiometabolic disease. The student will also perform functional validation experiments, including CRISPR/Cas9 genome editing, to investigate cardiometabolic disease mechanisms. In this project, the student will be exposed to a multidisciplinary environment, learning how to apply both experimental and computational approaches to study genetic factors contributing to human disease.

The successful candidate will be based in the Cebola, Randi and Birdsey labs at the Hammersmith Campus for the period of their study. They will join a cohort of Ph.D. students affiliated with the BHF Centres at Imperial, with particular interests in cardiovascular medicine and novel technologies.  They will also link to the wider Imperial College through multiple training opportunities provided throughout the course of the studentship.

To apply, you will need to complete the following step:

Please email Veena Dhulipala ( 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

The deadline to apply to this studentship is 23.59 on Sunday 8th March 2020. Interviews will be held in late March 2020. 

MRes/PhD studentships 20/21

Multidisciplinary discovery of new therapeutic targets

Ischemic heart disease (heart attack) is the foremost cause of death globally although current reperfusion therapies have dramatically increased immediate survival after ischemic disease, these therapies cannot restore the lost heart muscle cells (cardiomyocytes). Preventing death of cardiomyocytes would have immediate benefits to reduce infarct size (the damaged area) further improving survival as well as reducing the risk of future heart failure. The only definitive treatment for heart failure is heart transplantation, a solution available just to a restricted number of patients. Indeed, even small increases of infarct size correlate with considerable increased risk of mortality 1-year later including the risk of heart failure.

Previously, it was proposed to replace lost cardiac muscle cells with the transplantation of new cardiac progenitors which can subsequently repopulate the heart muscle.  Although long-term engraftment has proven very difficult to achieve in practise, grafting new cells into the heart after ischemic injury surprisingly still benefits long-term cardiac function. An evolving consensus is that transplanted cells contribute to heart cells survival and repair via signals they send out to existing cardiomyocytes. We recently found that signals secreted by progenitor cells prevent cardiomyocyte death following oxidative stress comparable to that seen during reperfusion of heart muscle following a heart attack. The secreted proteins suppressed programme cell death (apoptosis), reduced reactive oxygen content, and preserved mitochondrial function in human induced pluripotent cells (iPSC)-derived cardiomyocytes. This model provides a relevant human platform to investigate how extracellular signals augment cardiac muscle survival and cardioprotection.

You will take a multidisciplinary approach building on the unique skillsets of the collaborating labs to dissect the mechanisms mediating cardiomyocyte protection in a humanized model. You will learn to use our ischemia-reperfusion model to study the interactions between cardiac progenitor cells and iPSC-derived cardiomyocytes; learn and use proteomics approaches to study the intercellular signalling mediating cardiac muscle protection; and validate potential novel drug targets using gain and loss of function experiments with recombinant proteins, CRISPR/Cas9 gene editing, blocking antibodies and small molecule inhibitors.

Microfluidic platform for modeling of vascular changes

Pulmonary arterial hypertension (PAH) is a severe and currently incurable disorder characterized by progressive narrowing of small pulmonary arteries, leading to right heart failure. No single animal model can accurately reflect pathology of human PAH, severely limiting evaluation of drug treatment and characterization of disease mechanisms. Microfluidic devices are now being used to replicate physiological features of living human organs.

In this project we plan to develop a new microfluidic platform, which will allow simultaneous observation of different cell types interacting with vascular endothelium in arterioles and distal capillaries, altered in PAH. This multidisciplinary translational project will establish a model of lung peripheral vasculature with alveoli, using cells from PAH patients and healthy individuals, important in personalised medicine and drug testing.

The student will learn numerous cell biology, molecular biology (i.e. imaging, mediator analysis, gene expression analysis, manipulation of cells via oligos/siRNA/viral vectors and pharmacological agents) and nanofabrication techniques.