KESS2 East PhD in Mathematics: Combining mechanical modelling with image segmentation analysis to understand breast organoid formation
|Dyddiad cau cyflwyno cais||7 April 2019|
|Dyddiad dechrau||1 July 2019|
|Lefel astudio||Postgraduate research|
|Math o ddyfarniad||PhD studentship|
|Nifer o ysgoloriaethau ymchwil||1|
Combining mechanical modelling with image segmentation analysis to understand breast organoid formation.
Organoids are three-dimensional (3D) stem cell cultures that can self-organise into ‘mini-organs.’ They facilitate the study of tumour pathology to enable cancer drug discovery. Organoids are closer to in vivo tumours than more conventional 2D cell line cultures and can provide more relevant pharmacological responses to drugs and antibodies.
By using organoids in drug discovery screening assays, scientists can identify active compounds for further progression earlier in the drug discovery process and weed out less attractive compounds before incurring higher downstream costs.
Recently, Cellesce has developed imaging techniques that allow them to extract over 900 morphometric parameters of an organoid and, further, measure the influence of drug effects on these parameters. However, although effect identification and principle component analysis are good methods to begin with, as they highlight important correlations, they do not shed light on the mechanistic coupling between these components.
This project aims to use an advanced cell-based simulation software (CHASTE) to derive rules that will allow individual cells to reproduce and develop into organoid morphologies. Further, by linking the mechanistic properties to hormone signalling pathways we will be able to construct a fully 3D 'in silico' therapeutic testing bed.
Such a computational model provides a number of benefits, such as speeding up experimentation. Equally, a single computational model can be trivially parallelised allowing us to test new breast cancer therapies on their own, or in specific combinations allowing us to design optimal dosing strategies.
Critically, due to the use of donated tumour tissue, it is potentially possible to individualise the simulation results based on parameters extracted from a patient’s specific tissue, thus, providing personalised medical strategies.
The project's goals are to:
- review and develop an individual based model of an organoid that allows deformable geometry
- work with Cellesce to gain intuition as to how, and where, to include signalling proteins and their resultant mechanical coupling
- generate parameter sweeps used for comparing computational simulations to observed data in order to understand sensitivity and physical ranges for homeostatic conditions
- use approximate Bayesian computation to provide information on parameter sensitivity
- perform knock-out simulations, in which different mechanisms are deleted in order to identify a minimal set of physical processes that are needed to maintain observed morphologies
- simulate alterations in cell proliferation and differentiation after various treatments, to predict the resulting patterns of cell morphology for comparison with generated experimental data
- perform an extensive parameter sensitivity analysis in order to identify regions of parameter space in which drug responses occur
- work with Cellesce scientists to extract quantitative morphometric parameters from light sheet images of human breast cancer organoids
- refine the hypotheses of the mathematical models, as required, for the spatio-temporal dynamics of the organoid.
|Cefnogaeth Ffioedd Dysgu||Full UK/EU tuition fees|
|Tâl Cynhaliaeth||Doctoral stipend matching UK Research Council National Minimum|
|Preswylio||Applicants for these awards must have a home or work address in the relevant area* of Wales (East or West) at the time of their application for funding and enrolment.|
|Meini prawf academaidd||
Applicants for research PhDs are expected to have one or both of the following:
- have the right to work in the UK on completion of the scholarship
- be classified as a ‘home’ or ‘EU’ student
- satisfy the respective admissions criteria.
It is a condition of eligibility for KESS2 funding that you have not applied for, nor are intending to apply for, a doctoral or research master's loan. Please read clause (3) (m) of The Education (Postgraduate Doctoral Degree Loans) (Wales) Regulations 2018 for more information.
*The East Wales region is comprised of 7 local authorities: Cardiff, Flintshire, Monmouthshire, Newport, Powys, Vale of Glamorgan and Wrexham.
In the first instance, applicants should make initial enquiries via the named School / academic supervisor for each funded KESS2 project. All applicants must apply initially to the Doctor of Philosophy in Mathematics identifying the KESS2 Scholarship they wish to be considered for.
If deemed suitable for the project, applicants will be invited to complete a ‘KESS2 Participant Form’ which assesses eligibility for funding. Applicants must also be able to provide supporting documentary evidence of their eligibility. Guidance on this requirement is outlined in the KESS2 Participant Form, an example of which can be downloaded as above. Suitable applicants will be sent this form to complete following the School selection process. Further advice is available from the KESS2 team at email@example.com.
Rydym yn cadw'r hawl i gau cyfnodau ymgeisio’n gynnar, os bydd digon o geisiadau'n cael eu derbyn.
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