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Computational investigation of cell-shape signalling feedback during normal and pathological angiogenesis

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  • Full or part time
    Dr K Bentley
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

This 4-year PhD studentship is offered in Dr Katie Bentley Group based at the Francis Crick Institute (the Crick).

Our lab integrates computational and wetlab biology approaches to better understand the complex and often counter intuitive dynamics as endothelial cells coordinate and compete to grow new blood vessels. We are particularly interested in 1) how cell behaviour becomes maladaptive in disease and can it be therapeutically normalised? and 2) how cells exploit changes in their body shape to make faster and more reliable decisions during angiogenesis. We are actively focussed in the lab on untangling how abnormal vessels grow in eye disease. The abnormally enlarged, knotted vascular tufts that form during retinopathy of prematurity and diabetic retinopathy eventually cause mechanical traction, which can lead to irreversible blindness - so it is essential we find ways to limit and ideally reverse the abnormal growth of these vessels. Cell shapes and movements are dramatically altered in these abnormal vessels.

The specifics of the project can be developed in line with the candidates own skillset and interests, but an example project will ideally have one or more of these components:

developing/applying new mathematical or computational approaches to better simulate complex 3D cell shape-signalling feedback during cell migration as abnormal retinal vessels form.
developing mathematical/computational methods to predict new therapeutics to return cell behaviour to normal despite ongoing disease conditions.

For part 1 we expect that 3D agent-based, spring-mesh or similar biophysical-driven individual based modelling approaches will form part of the approach. For part 2 combinatorial perturbation studies, machine learning or other methods could be employed to creatively explore ways to manipulate cells behaviour in disease conditions.

All computer models and methods in the lab are expected to be developed alongside, and callibrated closely, to wetlab experiments performed by other members of our lab (for in vitro micropatterning/microfluidic cell experiments) and/or our international collaborators (for in vivo mouse retina and zebrafish experiments). We aim for all promising computational results/predicts will be tested in followup in vitro and in vivo experiments.

Candidate background
This position is ideal for an open, interdisciplinary minded candidate, with a strong background in mathematics, physics, computer science or a related discipline in order to work primarily, and relatively independently, on developing mathematical methods and writing simulation/analysis program code. Enthusiasm for biology and disease research is a must, however prior knowledge is not expected. A knowledge of image analysis is advantageous to integrate models well with the quantifications made from experiments.

An enthusiasm to learn new skills and gain experiences outside of your comfort zone (e.g. trying your hand at wetlab experiments to more deeply appreciate cell biology and understand the limitations of wetlab data) will be a definite advantage, as will enjoying working as part of a small cross-disciplinary team. Good communication skills are therefore essential.

As a lab we take an active interest in how our computational biology work at the cell level contributes to the wider fields of Artificial Intelligence and Psychology - considering how mechanisms of “intelligence” (adaptive behaviour) scale across organisms; an interest in this would be a plus.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 18 MARCH 2020. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Bentley, K., Philippides, A. and Ravasz Regan, E. (2014)

Do endothelial cells dream of eclectic shape?

Developmental Cell 29: 146-158. PubMed abstract

2. Bentley, K. and Chakravartula, S. (2017)

The temporal basis of angiogenesis.

Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 372: 20150522. PubMed abstract

3. Ubezio, B., Blanco, R. A., Geudens, I., Stanchi, F., Mathivet, T., Jones, M. L., . . . Gerhardt, H. (2016)

Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion.

eLife 5: e12167. PubMed abstract

4. Bentley, K., Gerhardt, H. and Bates, P. A. (2008)

Agent-based simulation of notch-mediated tip cell selection in angiogenic sprout initialisation.

Journal of Theoretical Biology 250: 25-36. PubMed abstract

5. Bentley, K., Mariggi, G., Gerhardt, H. and Bates, P. A. (2009)

Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.

PLOS Computational Biology 5: e1000549. PubMed abstract



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