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Immune cell re-programming as a therapy for lung disease. PhD in Medical Studies (GW4 BioMed MRC DTP)

  • Full or part time
  • Application Deadline
    Monday, November 25, 2019
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Supervisory team:
Dr Chris Scotton, Institute of Biomedical & Clinical Science College of Medicine & Health, University of Exeter
Dr Shaney Barratt, Faculty of Health Sciences, University of Bristol
Prof Mark Lindsay Faculty of Science, University of Bath
Prof Matt Whiteman, College of Medicine & Health, University of Exeter

Ageing populations have increased disease susceptibility, partly due to deteriorating immunity. We will use novel drugs to re-program the immune system, focusing on macrophages, to reduce the progression of deadly lung diseases – and track this using clinical samples, in vitro/in vivo models, next generation sequencing and advanced imaging.

Ageing is the biggest risk factor for serious, incurable and ultimately fatal lung diseases such as pulmonary fibrosis (PF) and chronic obstructive pulmonary disease (COPD). PF accounts for 1% of all UK deaths, while COPD is the 3rd biggest killer disease globally. Our ongoing analysis using the UK Biobank (a resource containing genetic, biomarker and health data for over 500,000 participants) has revealed exciting associations with immune cell numbers and also telomere attrition (which is a key feature of ageing) in PF and COPD. We have now begun replicating these findings in our joint Exeter-Bristol patient cohort. Monocyte/macrophages (MΦ) are key cells in PF and COPD. We now know that monocyte numbers predict mortality in patients. Effective immunity deteriorates with age, leading to immunosenescence and chronic low-grade inflammation (‘inflammageing’). This project will investigate monocyte/MΦ, their mitochondrial dysfunction (a key feature of ageing and PF) and PF development. We have exciting data showing that novel drugs developed by Prof Whiteman, which generate physiological doses of mitochondrial-targeted hydrogen sulfide, can ameliorate fibrosis in experimental model systems and also re-programme MΦ metabolism. H2S is depleted in PF.

Recent work from Prof Lindsay has further focused on the critical role of long non-coding RNA (lncRNA) in the regulation of inflammation in MΦ, while preliminary data from Dr Scotton’s group has demonstrated that adoptive transfer of human MΦ can exacerbate fibrotic disease in a murine model of PF. Taken together, our hypothesis is that “mitochondrial dysfunction in MΦ can be modified by our novel H2S drugs to alter cellular metabolism and transcriptome, facilitating tissue repair”.

There are 3 Aims:
1) Characterise the lncRNA transcriptome and phenotype of monocyte-derived macrophages from patients with PF versus age-matched (~60 year old) and young (~19-20 year old) controls using RNA-Seq, bioinformatics, and standard in vitro assays of the response to: a) inflammatory stimuli (i.e. cytokine release, chemotaxis, and phagocytosis) and b) macrophage polarisation e.g. M(LPS), M(IL4).
2) Interrogate the functional consequence of H2S supplementation on macrophage function and lncRNA levels in human MΦ, ± stimulation with LPS or IL-4 (to push cells toward an inflammatory or pro-fibrotic phenotype, respectively)
3) Determine the fibrogenic potential of young-vs-old human MΦ following adoptive transfer into immunocompromised NOD/SCID mice in an experimental in vivo model of PF, and the therapeutic benefit of our H2S drugs. Ultimately, we would like to translate these novel drugs from bench to bedside. Methodology: RNA-Seq; qRT-PCR; ELISA; flow cytometry of MΦ phenotype/function; Seahorse extracellular flux analysis; experimental mouse model of PF; In Vivo Imaging System (IVIS) tracking of fluorescently-tagged MΦ; measurement of lung collagen accumulation and ex vivo micro-Computed Tomography.

To apply for this project, please complete the application form at by 5pm Friday 25 November 2019.

Funding Notes

This studentship is funded through GW4 BioMed MRC Doctoral Training Partnership. It consists of full UK/EU tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£15,009 for 2019/20, updated each year) for 3.5 years.

For further information relating to the funding please see: View Website

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