Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, lung disease associated with high morbidity and median survival of <3 years. IPF incidence is rising and in critical need of novel avenues for therapeutic management. This project will enable us to understand the mechanisms that drive pathogenesis of IPF and may identify potential therapeutic strategies to limit or reverse disease progression.
Transforming growth factor-β (TGF-β) and integrin αVβ6 are key drivers of IPF, inducing epithelial-to-mesenchymal transition (EMT), myofibroblast activation and pathological matrix remodelling. Integrin αVβ6 promotes fibrosis by binding and applying mechanical force to latent TGF-β, inducing a structural change that releases the potent cytokine. Using novel proteomic approaches, we have found that αVβ6 signalling complexes recruit a mucin-galectin-3 regulatory module. MUC1 and galectin-3 also promote lung fibrosis and our iCASE partner has developed galectin-3-targeting drugs that inhibit TGF-β activity to suppress late-stage progression.
We now want to investigate how MUC1 and galectin-3 co-ordinate the ability of αVβ6 to drive TGF-β activation in IPF. Our collaborator identified a new mechanism by which MUC1 regulates integrin activation; the bulky glycoprotein funnels receptors into adhesions and applies compressive tension to activate integrins (Paszek et al. 2014). This new paradigm of integrin activation leads to our hypothesis: Galectin-3 and MUC1 co-ordinate αVβ6 trafficking and clustering to drive TGF-β activation during IPF pathogenesis.
1) Determine the impact of MUC1-galectin-3 interaction on αVβ6 trafficking and ligand engagement.
2) Analyse whether MUC1-galectin-3 interaction regulates αVβ6-medicated force application and TGF-β activation.
3) Test whether MUC1-galectin-3 interaction co-ordinates αVβ6 funnelling to drive TGF-β activation.
4) Determine whether MUC1-galectin-3-mediated regulation of αVβ6/TGF-β modulates response to galectin-3- and αVβ6-targeting drugs.
Together, these inter-disciplinary studies will reveal how αVβ6, MUC1 and galectin-3 co-operate to activate TGF-β; enabling us to understand mechanisms driving IPF pathogenesis and drug responses.
Supervisory team and training:
You will join a multidisciplinary supervisory team with expertise in mechanobiology and integrin-growth factor receptor crosstalk (Dr Mark Morgan), glycobiology and galectins (Prof Lu-Gang Yu), biomolecular engineering and interference microscopy (Dr Matthew Paszek, Cornell University, NY) and development of galectin-targeting drugs and IPF preclinical models (iCASE industrial partner, Galecto).
The project involves a range of advanced imaging techniques including super-resolution and live-cell imaging, traction force microscopy and topographical-scanning angle interference microscopy. Alongside these imaging approaches you will gain expertise in advanced data analyses and computational modelling. You will also learn a wide range of cell biological, biochemical and proteomic techniques and develop a novel in vitro organo-mimetic 3D model of IPF.
You will be based primarily in the Morgan Lab (www.morganlab.org; @M_MorganLab) in Liverpool, with opportunities to spend time at the Paszek Lab in the US (www.paszeklab.com) performing topographical-scanning angle interference microscopy and at Galecto’s research labs in Edinburgh (www.galecto.com) learning pre-clinical models of lung fibrosis.
Primary supervisor: Dr Mark Morgan; http://www.morganlab.org
Secondary supervisor: Prof Lu-Gang Yu; http://www.liv.ac.uk/translational-medicine/staff/lu-gang-yu/
Collaborator: Dr Matthew Paszek; http://www.paszeklab.com
iCASE industrial partner: Galecto; http://www.galecto.com
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
Adhesion and growth factor receptor crosstalk mechanisms controlling cell migration.
Thomas JR, Paul NR, Morgan MR.
Essays Biochem. 2019 Oct 31;63(5):553-567. doi: 10.1042/EBC20190025.
The cancer glycocalyx mechanically primes integrin-mediated growth and survival.
Paszek MJ, DuFort CC, Rossier O, Bainer R, Mouw JK, Godula K, Hudak JE, Lakins JN, Wijekoon AC, Cassereau L, Rubashkin MG, Magbanua MJ, Thorn KS, Davidson MW, Rugo HS, Park JW, Hammer DA, Giannone G, Bertozzi CR, Weaver VM.
Nature. 2014 Jul 17;511(7509):319-25. doi: 10.1038/nature13535.
Interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in human epithelial cancer cells.
Piyush T, Chacko AR, Sindrewicz P, Hilkens J, Rhodes JM, Yu LG.
Cell Death Differ. 2017 Nov;24(11):1937-1947. doi: 10.1038/cdd.2017.119.