Mitochondrial DAMPs triggering macrophage FPR1 ‘plaque’ receptor as a pathogenic factor in Crohn’s disease
Dr G Ho
Dr Calum Bain
Prof A G Rossi
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
The newly established four-year Medical Sciences & Translational Research PhD with integrated studies in Engagement for Impact Programme will combine medical science and translational research projects with integrated and credited teaching in science communication, public engagement, patient involvement, data design and informatics, via established MSc courses and/or new Engagement for Impact courses. Our vision is to teach a generation of researchers equipped to address and solve real-world problems through excellent science and who have the engagement and impact skills we believe will give them an edge in their future careers.
This potential PhD project, selectable by successful applicants to this Programme, is supervised by Dr Gwo-tzer Ho (www.cir.ed.ac.uk/investigator/Dr-Gwo-Tzer-Ho) at the Centre for Inflammation Research, with co-supervisors Dr Calum Bain and Prof Adriano Rossi.
Crohn’s disease (CD) is a debilitating and incurable condition, which is projected to affect 10 million individuals by 2025. We aim to investigate the role of mitochondrial formylated peptides (mFPs) as a host-derived damage associated molecular pattern (DAMP) in innate immunity1. Mitochondria, intracellular organelles responsible for cellular energy production, are descended from bacteria. They have autonomous protein synthesis machinery, with mFPs similar to bacteria. When released extracellularly, they are recognised by formylated peptide receptor-1 (FPR1), which is evolutionarily considered as the receptor for Yersinia pestis, the causative bacteria for the plaque2. Recent Western pandemics (e.g. Black Death) with high mortality have shaped population genetics as variants of FPR1 gene can protect against plaque. This is less relevant with the discovery of antibiotics. In parallel, CD has emerged as a major disease-entity in the 20th century. Of interest, human genetic and transcriptomic studies point to a role of FPR1 in the macrophage in CD3,4. We have shown that: (1) High levels of mFPs are found in active disease; (2) Recruited monocyte-macrophage populations in CD are marked with high FPR1 expression; (3) FPR1-deletion is protective in experimental colitis. These data provide the hypothesis that abnormal FPR1 activation by host-derived mFPs (as opposed to bacteria) is a key pathogenic factor that shapes the pro-inflammatory phenotype of the macrophage and importantly, is a therapeutic target for CD.
In this PhD, the applicant will investigate (1) the mechanisms of mFPs on monocyte-macrophage function, (2) the influence of genetics on mFP-FPR1 signalling and (3) the translational potential of modulating this pathway in CD. This project will have a strong focus on human CD subjects with mouse transgenic work in the Gut Research Unit with macrophage (Calum Bain) and FPR1-signalling (Adriano Rossi) experts.
1. Boyapati RK, … Ho GT. Gut mucosal DAMPs in IBD: from mechanisms to therapeutic implications. Mucosal Immunology. 2016 May; 9(3):567-82.
2. Osei-Owusu P et al. FPR1 is the plague receptor on host immune cells. Nature. 2019 Oct;574(7776):57-62.
3. Peters LA et al. A functional genomics predictive network model identifies regulators of inflammatory bowel disease. Nature Genetics 2017 Oct;49(10):1437-1449.
4. Martin JC et al. Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy. Cell. 2019 Sep 5;178(6):1493-1508.e20
Engagement for Impact:
In this project, the PhD applicant will be given the opportunity to:
• Develop a dedicated PPI program where patients/participants are embedded in our Science-to-Medicine work.
• This group will be allowed to follow our laboratory progress meetings with a prospect to offer scientific direction, first-hand interaction with data and oversight into future clinical studies.
• The PhD applicant will work with one of our current PPI patient (a training journalist) to develop a public-facing regular media forum (3-4 months) with ‘on the ground’ updates on our IBD work, from a patient and scientist perspective.
• This plan will have an expansive theme from basic science (the lab), ideas and data (lab meeting), human studies (in the hospital), the scientific process (what happens after a patient donates his/her sample) to the clinical trial (the workings of our drug trials team).
• The main target will be IBD patients, public participants in any scientific studies but this platform can be opened up to secondary school students, teachers and career development teams.
The aim is to put the patients at the heart of the dynamic progress of our scientific work. The candidate will work alongside our existing IBD and also CIR PPI team.
This is one of the potential projects in the University of Edinburgh College of Medicine and Veterinary Medicine’s new 4 year Medical Sciences & Translational Research PhD with integrated studies in Engagement for Impact Programme. Successful applicants will select their preferred PhD projects from the available options in discussion with proposed supervisors. Three studentships are available in the programme, providing full tuition fees (EU/UK rate only), stipend of at least £15,000 per year, £450 annual travel and conference allowance, dedicated engagement support grant of £1,500, and £5,000 annually towards research consumable costs.
Apply before 26th January 2020 at https://www.ed.ac.uk/inflammation-research/postgraduate-training/phd-programme