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Dissecting receptor crosstalk mechanisms that co-ordinate wound healing and drive scar formation

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  • Full or part time
    Dr M Morgan
    Dr I Karakesisoglou
    Prof L Yu
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

This project will enable us to understand mechanisms regulating wound healing and may identify therapeutic strategies to limit scar formation.

TGF-β and integrin αVβ6 are key drivers of wound healing, inducing epithelial cell migration, myofibroblast activation, wound contraction and matrix remodelling. Integrin αVβ6 activates TGF-β by binding and applying forces to latent TGF-β, inducing a structural change that releases the potent cytokine. Using proteomic approaches, we found that αVβ6 signalling complexes recruit a mucin-galectin-3 regulatory module. MUC1 and galectin-3 also regulate wound repair and our iCASE partner has developed galectin-3-targeting drugs that inhibit TGF-β activity in vivo.

We want to investigate how MUC1 and galectin-3 co-ordinate the ability of αVβ6 to drive TGF-β activation during wound healing. 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. 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 wound healing.

Objectives:
1) Determine impact of MUC1-galectin-3 interaction on αVβ6 trafficking and ligand engagement.
2) Analyse whether MUC1-galectin-3 interaction regulates αVβ6-mediated 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.

These inter-disciplinary studies will reveal how αVβ6, MUC1 and galectin-3 co-operate to activate TGF-β; enabling us to understand mechanisms driving wound healing, tissue regeneration and scar formation.

Supervision and training:
You will join a multidisciplinary supervisory team with expertise in mechanobiology and receptor crosstalk (Dr Mark Morgan), skin biology and wound healing (Dr Akis Karakesisoglou), glycobiology and galectins (Prof Lu-Gang Yu), biomolecular engineering and interference microscopy (Dr Matthew Paszek, Cornell University) and development of galectin-targeting drugs and preclinical models (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 and biochemical techniques and develop a novel in vitro organo-mimetic 3D model of wound healing.

You will be based in Dr Mark Morgan’s lab in Liverpool, with opportunities to spend time at the Paszek Lab in the US performing topographical-scanning angle interference microscopy, Dr Akis Karakesisoglou’s lab in Durham developing 3D skin mimetics and at Galecto’s research labs in Edinburgh learning pre-clinical models.

Lead supervisor: Dr Mark Morgan; http://www.morganlab.org; @M_MorganLab
Second supervisor: Dr Akis Karakesisoglou https://www.dur.ac.uk/biosciences/about/schoolstaff/profile/?mode=staff&id=5516
Third 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


HOW TO APPLY

Applications should be made by emailing [Email Address Removed] with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to [Email Address Removed]

Funding Notes

This is a 4 year BBSRC CASE studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Self-Assembling Proteins as High-Performance Substrates for Embryonic Stem Cell Self-Renewal. Advanced Materials (Impact Factor: 25.81). 2019 Mar 13:e1807521

Intrinsic tryptophan fluorescence spectroscopy reliably determines galectin-ligand interactions. Scientific Reports. 2019 Aug 14;9(1):11851

Bioengineering the microanatomy of human skin. Journal of Anatomy. 2019 Apr;234(4):438-455

Physical Principles of Membrane Shape Regulation by the Glycocalyx. Cell. 2019 Jun 13;177(7):1757-1770.e21

Integrin αVβ6-EGFR crosstalk regulates bidirectional force transmission and controls breast cancer invasion BioRxiv. 2018 doi: 10.1101/407908

Pro-migratory and TGF-β-activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated through an Eps8-dependent GTPase switch Journal of Pathology. 2017 Jun 13 10.1002/path.4923

Interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in human epithelial cancer cells. Cell Death & Differentiation. 2017 Nov;24(11):1937-1947

p63 transcription factor regulates nuclear shape and expression of nuclear envelope-associated genes in epidermal keratinocytes. Journal of Investigative Dermatology. 2017 137(10): 2157-2167

PPFIA1 drives active α5β1 integrin recycling from the TGN to control fibronectin fibrillogenesis and vascular morphogenesis Nature Communications. 2016 Nov 7:13546

The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Nature. 2014 Jul 17;511(7509):319-25

Syndecan-4 phosphorylation is a control point for integrin recycling Developmental Cell. 2013 Mar 11;24(5):472-485

A syndecan-4 hair trigger initiates wound healing through caveolin- and RhoG-regulated integrin endocytosis Developmental Cell. 2012 Nov 13;23(5):1081-2



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