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(BBSRC DTP) Regulation of cell division by mechanical force in tissues: speed versus strength


Faculty of Biology, Medicine and Health

About the Project

The cells and tissues of our bodies are constantly being pushed and pulled and it is vital that they sense and respond to these mechanical forces appropriately to maintain normal tissue function1. Whilst we are beginning to understand some of the cellular mechanisms that link cell behaviour with mechanical force in isolated cells, we know much less about how this applies to the complex tissues of our bodies. Bridging this gap is important considering the significant mechanical changes that take place in tissues as they are formed and shaped in the embryo and as they age and become diseased (e.g. via cancer) in the adult.

In this project, we will investigate how a fundamental cellular function – cell division – is regulated by mechanical force in a complex embryonic tissue. In recent work, we have shown that epithelial cells are exquisitely sensitive to low levels of stretching (tensile) force, which increases their cell division rate and reorients divisions along the axis of stretch2. For this PhD project, we will build on these findings to ask a crucial question: how does the speed of a stretch alter the regulation of cell division? This is important because all studies to date have focused on fast stretches of cells, which don’t reflect the slower stretches that most commonly occur in embryonic and adult tissue. In preliminary data we find marked differences in how a tissue responds to slow versus fast stretches. These results have the potential to change how we think about mechanical regulation of cells and tissues.

For their PhD, the student will:
1. Use live confocal microscopy to image cell division in stretched and unstretched tissue.
2. Develop/apply mathematical modelling to understand patterns of mechanical force in tissue3,4.
3. Determine how the regulation of the actin cytoskeleton and membrane tension5 control tissue responses to force.

This is an interdisciplinary project that is well-suited to students from a wide range of academic disciplines: biological, mathematical and physical. The exact content of the project can be adapted according to the academic background of the selected candidate and will provide a solid foundation in cell and developmental biology and its intersection with biophysics and mathematics. The student will build a diverse and novel skill set, combining embryology, advanced microscopy and cutting-edge mathematical/computational analysis and will benefit from supervision by a team of scientists who bring complementary areas of expertise and years of experience supervising interdisciplinary projects of this kind.

https://www.wellcome-matrix.org/people/sarah-woolner/
https://www.wellcome-matrix.org/people/pat-caswell/
https://personalpages.manchester.ac.uk/staff/oliver.jensen/

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

1. Heisenberg, C. P. & Bellaiche, Y. (2013) Forces in tissue morphogenesis and patterning. Cell 153, 948-962.
2. Nestor-Bergmann, A., Stooke-Vaughan, G.A., Goddard, G.K., Starborg, T., Jensen, O.E. and Woolner, S. (2019) Decoupling the roles of cell shape and mechanical stress in orienting and cueing epithelial mitosis. Cell Reports 26: 2088-2100.
3. Nestor-Bergmann, A., Goddard, G., Woolner, S. and Jensen, O.E. (2017) Relating cell shape and mechanical stress in a spatially disordered epithelium using a vertex-based model. Mathematical Medicine and Biology. 35 (Supplement 1) 1-27
4. Jensen, O.E., Johns, E. and Woolner, S. (2020) Force networks, torque balance and Airy stress in the planar vertex model of a confluent epithelium. Proceedings of the Royal Society A, 476: 2237.
5. Hetmanski, J. H. R., de Belly, H., Nair, R.V., Sokleva, V., Dobre, O., Cameron, A., Gauthier, N., Lamaze, C. and Swift, J. and del Campo, A. and Paluch, E. and Schwartz, J. and Caswell, P.T. (2019) Membrane Tension Orchestrates Rear Retraction in Matrix Directed Cell Migration. Dev. Cell Nov 18;51(4):460-475.e10.

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