Building a Toxicological Screen to Predict Drug-Induced Pulmonary Hypertension at University of East Anglia

Pulmonary arterial hypertension (PAH) is a debilitating, often fatal disease, affecting both children and adults, which is caused by structural changes (vascular remodelling) of pulmonary blood vessels leading to their narrowing and obliteration (PMID:15194174). PAH can be caused by both genetic and environmental factors, including drug-induced PAH (PMID:31406341; PMID:29508628). There is currently no cure for PAH therefore any off-target effects of drugs can have devastating effects on affected individuals. As new drugs and modalities are developed the toxicological effects of off-target drug-induced PAH is becoming an increasing burden in drug development in the respiratory and oncology therapy areas and a cause for failures in clinical trials.This compounded by the observation that animal models are not optimal for recapitulating off target effects of human PAH-inducing drugs. Therefore, there is a need to develop human in vitro systems that can be used in toxicological approaches for PAH. A specific bio-marker of diease is reduced in all forms of PAH in humans as well as in in vivo and in vitro models of disease at both the transcriptional and protein levels (PMID:3140634). These reduced levels are proportional to disease susceptibility. Therefore, tracking the expression levels of this bio-marker can be used as surrogate for susceptibility to PAH.

Our aims are:

1. Generate a stable CRISPR mediated knock-in reporter line in induced pluripotent stem cells (iPSCs),
2. Validate reporter expression and responsiveness of iPSC-derived endothelial and smooth muscle cells to drugs known to cause PAH
3. Set-up and validation of an iPSC-based pulmonary artery-on-a-chip to observe reporter expression levels as a surrogate for drug-induced PAH

This project is a collabortion between UEA and AstraZeneca. The successful applicant will be expected to work across both academia (42 months) and industry placement (Cambridge, 6 months) in a highly supportive and inclusive learning environment.

Funding

This PhD studentship is funded by a MRC ITTP studentship with AstraZeneca for four years. Applications are welcomed from those eligible for ‘home’ tuition fees only. Funding consists of home tuition fees, an annual stipend of £17,668 (for a maximum of 48 months).