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DiMeN Doctoral Training Partnership: A combined experimental and computational approach to understand spatial ordering of cell lineages within tissues.

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  • Full or part time
    Dr N Akhtar
    Dr A Fletcher
    Prof S Winder
  • 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

Mammary gland epithelium is spatially ordered as a bilayer of inner secretory luminal epithelia and outer myoepithelia bordering a laminin-rich basement membrane (BM). However, a key unanswered question in biology is how different cell lineages self-organize into their positions. Understanding this is of central importance because correct concentric arrangement of cells within tissues is crucial for normal tissue function and failure to organize properly might contribute to architectural defects associated with cancer. Myoepithelia contribute significantly to BM deposition and are frequently absent from the outer edge of advanced breast tumours.

Integrins and dystroglycans are transmembrane receptors that detect the BM on the outside of cells and link to actin-myosin networks inside cells. Myoepithelia express higher levels of integrins and dystroglycans compared to luminal cells, which might act as a driving force to position these cells to the outside. This project will test the hypothesis that cell-BM affinity facilitates self-organisation within tissues.

The project will use an interdisciplinary approach, combining experimental and computational techniques to address whether altering different integrin levels in either mammary cell lineage alters cell positioning and thereby tissue structure. Cre-Lox technology will be used to analyse the consequences of lineage-specific β1-integrin removal on cell positioning and cell division axis orientation in mammary gland tissue in vivo. In parallel, cutting edge primary co-culture organoids of myoepithelial and luminal cells that mimic in vivo tissues will be used to deconstruct the mechanism. The project will utilize various genetic manipulation tools including lentiviral expression and shRNA, Cre-Lox technology, 4D live imaging of distinct GFP labeled cell lineages and immunofluorescence staining with 3D image rendering to attain data.

Computational modelling of co-culture organoid growth in the wildtype and perturbed settings will be used to assess the integrin/dystroglycan-specific relative adhesion between myoepithelial and luminal cells and the BM.
The project will suit a biologist with a strong interest in mathematical modelling. Candidates should have, or expect to achieve a minimum of 2:1 Honours degree (or equivalent) in Biological Sciences or related discipline.

Informal enquiries can be made to Dr Nasreen Akhtar ([Email Address Removed]).

Funding Notes

This studentship is part of the MRC Discovery Medicine North (DiMeN) partnership and is funded for 3.5 years. Including the following financial support:
Tax-free maintenance grant at the national UK Research Council rate
Full payment of tuition fees at the standard UK/EU rate
Research training support grant (RTSG)
Travel allowance for attendance at UK and international meetings
Opportunity to apply for Flexible Funds for further training and development
Please carefully read eligibility requirements and how to apply on our website, then use the link on this page to submit an application: http://www.dimen.org.uk/how-to-apply/application-overview


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