GW4 BioMed MRC DTP PhD Studentship: Blood-borne microparticles: Enigmatic cell-derived vesicles with a causal role in skin and lung fibrotic diseases?

This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ which is offering up to 19 studentships for entry in September/October 2018.

The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities. The training programme has three strands: research skills; professional and career development skills; and opportunities to broaden horizons, which might include placements, research visits, public engagement internships and a mini-MD programme of bespoke clinical exposure.

Supervisory team for this project:
Dr John Pauling (Bath), Dr Shaney Barratt (Bristol), Dr Giordana Pula (Exeter) and Prof Mark Lindsay (Bath)

Project description:

Systemic sclerosis (SSc) is a multisystem disease characterised by autoimmunity, vasculopathy and fibrosis. Fibrosis within the lungs (interstitial lung disease, ILD) is the major cause of disease-related morbidity and mortality in SSc but does not occur in all patients. Idiopathic pulmonary fibrosis (IPF) is a related fibrosing disease of the lung. Mechanisms driving fibroblast activation in these diseases is poorly understood. There is an unmet need for biomarkers of disease activity and progression.

Circulating microparticles (MPs) are membrane-bound vesicles shed from the surface of a variety of cells including platelets, endothelial cells, epithelial cells and leukocytes (each implicated in the pathogenesis of both SSc and IPF). We hypothesise MPs play an important role in intercellular communication; transporting proteins, mRNA and non-coding microRNA to effector cells within sites of tissue injury. We have recently identified differences in MP subpopulations in SSc compared with other connective tissue diseases (n~20 per group was sufficient to identify inter-group differences in cellular origin, BBA Clin. 2016;10:16-22). MP populations and their contents have not been examined in SSc-ILD or IPF.

This multi-disciplinary, cross-institutional studentship shall use cutting edge technologies (including nanoparticle tracking analysis [NTA], proteomics and transcriptomics) to evaluate the source, contents and putative biological action of circulating MPs in SSc and IPF. We hypothesise: 1) specific MP subpopulations differ between healthy controls, IPF and SSc (with or without ILD) and 2) MPs are an important source of protein and mRNA drivers of fibrosis.

Our principal aims are:
(1) Isolate circulating MPs from blood samples of patients with SSc (no ILD), SSc (with ILD), IPF and healthy controls using NTA (n=20 per group).
(2) Proteomic and transcriptomic characterisation of MP subpopulations obtained from patients with SSc (no ILD), SSc (with ILD), IPF and healthy controls (n=8 taking account expected time/cost considerations), to identify disease-related MP protein and RNA signatures across these disease states.
(3) If enrichment analysis identifies specific protein or mRNA signatures, further interrogation of the functional role of MPs from the disease/control groups on fibroblast function (e.g. proliferation, migration and activation) shall be explored using in vitro models.
(4) If phase 3 gives positive results, investigation of the putative molecular pathways driving functional changes shall be explored in vitro.

The successful student shall have access to existing samples (plasma and explanted fibroblasts) from well characterised SSc and IPF patient cohorts (JP, SB) allowing immediate commencement of laboratory work. He/she shall gain expertise in routine biochemical analytical techniques (e.g. Immunoblot and ELISA), primary cell culture (SB, Bristol and Dr Chris Scotton, Exeter) and cutting edge methods available within this cross-disciplinary GW4 network collaboration including NTA (GP, Exeter), proteomics (Dr Kate Heesom, Bristol) and transcriptomics (ML, Bath, including Bioinformatics expertise).


IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form. More information on the application process may be found here: http://www.gw4biomed.ac.uk/projects-2/for-students/

APPLICATIONS OPEN ON 25 SEPTEMBER AND CLOSE AT 17:00 ON 24 NOVEMBER 2017.

You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Bath.