Phd in Multiscale Modelling of Endothelial Cell Monolayers in Health and Disease

Do you have a passion for life sciences, physiology, or medicine and are eager to employ computational science methods to study endothelial cells in the microcirculation?

The Computational Science Lab (CSL) within in the Informatics Institute is offering a PhD position focusing on multiscale modelling of Endothelial Cell (EC) monolayers in the microvasculature, coupling molecular models of intracellular signalling to cell-level models of spatially resolved signalling, and finally to coupling many of such single cell-level models together in a multicellular EC monolayer. The goal is to study specific pathways (based on RhoA and RhoB GTPases) and their impact on EC monolayer integrity. You will study differential pathways that drive fast and transient (RhoA-mediated), or slow and persistent (RhoB-mediated) loss of endothelial integrity. You will merge in silico modelling with in-vitro experiments carried out in close collaboration with another PhD student in this joint project to address bistability and hysteresis in the differential RhoA/B-dependent control of microvascular leak. You will study cell-to-cell variability in responses to activating stimuli and address the switch from acute to chronic EC activation.

The research will be carried out in close collaboration with the physiology group of Prof. Peter Hordijk at the Free University Amsterdam, where the lab experiments will be carried out. You will spend sufficient time in prof. Hordijk’s lab to foster strong collaboration with the experimental work, and vice-versa, the PhD student carrying out the experimental work will spend sufficient time in our Computational Science lab to work together with you.

What are you going to do?

The aims of your project are:

• To develop and implement a sub-cellular model of the RhoA/RhoB pathways using lumped parameter ODE based models. Next, to develop and implement a spatiotemporal model of signalling in the sub cellular space in a single EC, using compartmentalised models. And finally, to develop and implement a model of an EC monolayer, using cellular Potts models and integrate the earlier mentioned spatiotemporal models of signalling in a single EC.
• To parameterize and validate your models based on the experimental results. And vice-versa, to inform new experiments based on your simulations.
• To study the dynamical properties of the sub-cellular model, e.g. its stable states, or bistability, and hysteresis. Also to obtain, by model fitting on experimental data, the model parameters for different types of EC to explain cell-to-cell and cell type heterogeneities. With the single cell spatiotemporal EC model you will first reproduce experimentally observed spatiotemporal oscillations of RhoB activation and then study the dynamics of quiescent EC as well as under pro-inflammatory conditions. Finally, with the EC monolayer model you will study heterogeneities in EC monolayers, fluctuations, and frequency of gap formations, and on the difference between quiescent and inflamed monolayers, explicitly including mechanics of the monolayers. Additional data obtained using plasma samples from Chronic Kidney Disease patient samples will be incorporated, to allow translation of the mathematical model to the (pre)clinical situation.

For setting up the mathematical models and simulations you will rely as much as possible on existing (python based) toolkits such as PySB (pysb.org) for modelling the signalling pathways, and the Compucell3D for the EC monolayer simulations (compucell3d.org). Inclusion of blood flow modelling you will rely on Palabos (palabos.unige.ch) and our own Hemocell framework (hemocell.eu). For the multiscale coupling you will use packages such as Muscle3. Most programming will be in Python and/or C++.

What do you have to offer?

Your experience and profile

You will have:

• a first master degree or equivalent in computational science, computional biology, computational (bio)physics, applied mathematics, or an allied field;
• research experience in applying in-silico modelling in the life sciences, physiology, or medicine;
• proven programming expertise in python or c++;
• motivation and ambition to work in a challenging and interdisciplinary research team;
• a good command of English;
• affinity with cell biology and interested to learn wet-lab techniques.

Our offer

A temporary contract for 38 hours per week for the duration of 4 years (the initial contract will be for a period of 18 months and after satisfactory evaluation it will be extended for a total duration of 4 years). The preferred starting date is as soon as possible. This should lead to a dissertation (PhD thesis). We will draft an educational plan that includes attendance of courses and (international) meetings. We also expect you to assist in teaching undergraduates and master students.

The gross monthly salary, based on 38 hours per week and dependent on relevant experience, ranges between € 2,770 in the first year to € 3,539 in the last year (scale P). UvA additionally offers an extensive package of secondary benefits, including 8% holiday allowance and a year-end bonus of 8.3%. The UFO profile PhD Candidate is applicable. A favourable tax agreement, the ‘30% ruling’, may apply to non-Dutch applicants. The Collective Labour Agreement of Universities of the Netherlands is applicable.

Besides the salary and a vibrant and challenging environment at Science Park, we offer you multiple fringe benefits:

• 232 holiday hours per year (based on fulltime) and extra holidays between Christmas and 1 January;
• Multiple courses to follow from our Teaching and Learning Centre;
• A complete educational program for PhD students;
• Multiple courses on topics such as leadership for academic staff;
• Multiple courses on topics such as time management, handling stress and an online learning platform with 100+ different courses;
• 7 weeks birth leave (partner leave) with 100% salary;
• Partly paid parental leave;
• The possibility to set up a workplace at home;
• A pension at ABP for which UvA pays two third part of the contribution;
• The possibility to follow courses to learn Dutch;
• Help with housing for a studio or small apartment when you’re moving from abroad

About us

The University of Amsterdam (UvA) is the Netherlands' largest university, offering the widest range of academic programmes. At the UvA, 42,000 students, 6,000 staff members and 3,000 PhD candidates study and work in a diverse range of fields, connected by a culture of curiosity.

The Faculty of Science (FNWI) has a student body of around 8,000, as well as 1,800 members of staff working in education, research or support services. Researchers and students at the Faculty of Science are fascinated by every aspect of how the world works, be it elementary particles, the birth of the universe or the functioning of the brain.

The mission of the Informatics Institute (IvI) is to perform curiosity-driven and use-inspired fundamental research in Computer Science. The main research themes are Artificial Intelligence, Computational Science and Systems and Network Engineering. Our research involves complex information systems at large, with a focus on collaborative, data driven, computational and intelligent systems, all with a strong interactive component.