Current Opportunities


Donald Heath Ph.D. Studentships 2018-2021

Background and Applications Instructions

You will participate and develop in the exciting Donald Heath pulmonary hypertension research programme. This multi-disciplinary programme combines clinicians and clinician scientists with biologists, physicists and engineers based at the University of Sheffield and Royal Hallamshire Hospital, Sheffield towards the better understanding of the mechanisms driving Pulmonary Hypertension, and improved patient care.  The successful candidate will undertake research towards a PhD in the Department of Infection, Immunity & Cardiovascular Disease, Faculty of Medicine Dentistry & Health.  There is 1 fully funded PhD studentship available to work on one of the projects listed below with the named supervisors. Interested candidates are encouraged to make contact with the primary supervisor to discuss their application before applying. Applications are made by the complete of both the Donald Heath PhD Application Form_2018-19 the University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply.

Available Projects and Supervisors

Project Title:  The Role of SMURF1 in Pulmonary Arterial Hypertension.
Project Title: Identification of blood-based epigenetic and immunological biomarkers for personalising PAH treatments.
Project Title: Investigating the role of Filamin A in pulmonary artery smooth muscle and endothelial cell phenotype.
Project Title: Investigating the role of the OPG/TRAIL axis in right ventricular remodeling.
Project Title: Hyperpolarized xenon MRI for assessment of gas exchange and perfusion limitation in pulmonary hypertension.



Project Title:
The Role of SMURF1 in Pulmonary Arterial Hypertension.
Primary Supervisor: Dr Alex Rothman
Secondary Supervisor: Professor Sheila Francis

Hypothesis:
SMURF1 is expressed in specific cells of the pulmonary vasculature and cell specific deletion of SMRUF1 will protect from the development of experimental pulmonary arterial hypertension.

Summary Paragraph:
Pulmonary arterial hypertension (PAH) is a devastating disease in which progressive pulmonary vascular remodelling leads to right heart failure and death. Current therapies target vascular constriction, however not all patients benefit from treatment and the cellular proliferation that drives disease persists. Novel anti-proliferative therapies are required and strategies to match patients to treatments would provide clinical benefit and reduce healthcare costs. We have recently demonstrated that SMAD-specific ubiquitin ligase regulatory factor-1 (SMURF1) is critical to pulmonary vascular remodelling in experimental PAH, and that SMURF1 expression is increased in blood from patients with PAH. The proposed studies will determine the vascular cell type in which expression of SMURF1 is important to PAH using transgenic and animal models of PAH and determine mechanisms though which SMURF1 mediates disease pathology using cell culture and novel small molecule inhibitors of SMURF1. An appropriate candidate will gain experience of cell culture, animal models, bioinformatics, data handling and presentation and writing for publication.



Project Title:
Identification of blood-based epigenetic and immunological biomarkers for personalising PAH treatments.
Primary Supervisor: Dr Dennis Wang
Secondary Supervisor: Dr Allan Lawrie

Hypothesis:
RNA markers in whole blood are predictive of PAH treatment response and can be used as a companion diagnostic to stratify patients.

Summary Paragraph:
This project will generate epigenetic and immunologic markers existing in whole blood samples that are predictive of clinical outcomes to underpin patient stratification and the selection of targets for drug development.

Through the analysis of whole blood RNAseq obtained from existing samples (500 patients and 100 controls – ongoing) we will determine (a) specific differences in gene expression in PAH from controls; (b) the relationship to non-coding variants from matched WGS patients (eQTL analysis); (c) the relationship to immune cell-type specific expression; (d) and deveop a multivariate classifier to stratify the patient cohort. Differentially expressed genes identified from RNAseq will be mapped to non-coding variants using epigenetic markers from ENCODE. Immune specific signatures from MsigDB will also be used to deconvolute the whole blood RNA signal to get relative proportions of immune cell components. Both the epigenetic and immune associated gene expression will be integrated with SomaLogic protein markers. Gene signatures will be generated using machine learning approaches to determine gene patterns relating to phenotype, treatment response and clinical outcome.



Project Title:
 Investigating the role of Filamin A in pulmonary artery smooth muscle and endothelial cell phenotype.
Primary Supervisor: Dr Allan Lawrie
Secondary Supervisor: Dr Rob Wilkinson

Hypothesis:
Filamin A is a key actin binding protein critical to normal BMP signalling and pulmonary vascular cell phenotype.

Summary Paragraph:
Mutations in Filamin A (flna) have been found in patients with Idiopathic Pulmonary Arterial Hypertension (IPAH), and pilot transcriptomic data suggest flna is the most highly expressed gene in whole blood from patients with IPAH. Flna is a key scaffold protein with multiple protein binding partners related to cytoskeletal organisation and intracellular signalling. Of particular interest to the PAH is the interaction with Smads (downstream of BMP). This project will use patient cells, and normal cells with mutations induced using CRISPi to dissect the molecular mechanism of these mutations in vitro. Further investigation of flna in PAH will be investigated in zebrafish (CRISPRi) and mouse (flnafl/fl) models to determine the molecular mechanisms of the causal role for flna mutations in PAH.



Project Title: 
Investigating the role of the OPG/TRAIL axis in right ventricular remodeling.
Primary Supervisor: Dr Allan Lawrie
Secondary Supervisor: Dr Roger Thompson

Hypothesis:
OPG and TRAIL contribute to right ventricular remodelling independent of pulmonary vascular remodelling.

Summary Paragraph:
Although severe and progressive pulmonary vascular remodelling drives the haemodynamic alterations that occur in PAH, PAH is a multi-organ disease and the ability of the right ventricle (RV) to cope with these alterations varies by patient. Almost all eventually die from right heart failure. It is therefore important to assess whether any phenotypic effects observed from the loss of a ‘OPG or TRAIL’ are due solely to effects on pulmonary vascular remodelling, or in combination with ventricular remodelling. RV pressure overload will be induced by surgical banding of the main pulmonary artery causing RV hypertrophy in the absence of any underlying pulmonary vascular remodelling, and without influence from soluble factors secreted form the remodelling pulmonary vasculature. (e.g. OPG). The initial screen will be for an altered RV phenotype following global deletion (PGK-cre+/tg) followed by mice with ventricular specific (MLC2v-cre+/tg) deletion will be assessed in two models, the PAB and SuHx mouse model described above.



Project Title: 

Hyperpolarized xenon MRI for assessment of gas exchange and perfusion limitation in pulmonary hypertension.

Primary Supervisor: Professor Jim Wild 
Secondary Supervisor: Professor David Kiely – clinical

Hypothesis:
Hyperpolarised xenon MRI can provide novel insight in to ventilation, perfusion and alveolar-capillary gas exchange. Our pilot data with the method suggest it has sensitivity to provide quantitative information that can help distinguish subgroups of pulmonary hypertension eg distinguish interstitial changes in PH-SSc and hemodynamic changes related to post-capillary disease in PVOD.

In this project we will recruit a non-clinical MRI scientist PhD student to work on further development of dissolved phase xenon imaging techniques for quantitative assessment of alveolar-capillary gas exchange in PH. We will then evaluate the methods alongside established proton MRI methods for contrast enhanced perfusion imaging in cohorts of patients recruited from the SPVDU with subgroups of PH.

Summary Paragraph:
The student will be a physicist/engineer based in the POLARIS group under the supervision of Jim Wild and will liaise closely with the SPVDU and clinical fellows working in this field.