A systems biology approach to analyse signalling and trafficking patterns of CXCR4 and ACKR3

Early stage researcher 12 (ESR12) project
Supervision: Dr. Maria Waldhoer, Dr. Aurelien Rizk
Host: InterAx Biotech AG

I – Project proposal:

Aim:

  1. To assess the signalling and trafficking patterns of CXCR4 and ACKR3 using real time kinetic assays
  2. To design a systems biology mathematical model to derive novel kinetic parameters from the experimental data.

Methodology:
This project will focus on the use of Systems biology as a computational tool to integrate theoretical knowledge of signal transduction pathways with experimental data of CXCR4 and ACKR3 mediated signaling and trafficking events. As a result, deeper mechanistic insights into the dynamic cellular signaling systems activated by these receptors will be gained. Ligands will be tested in house using i) real-time kinetic signaling assays (cells expressing CXCR4 or ACKR3 and biosensors like EPAC for cAMP measurements or Calcium release assays) and ii) real-time internalization/recycling assays (TR-FRET based assays) and in the partner laboratories UNOTT and VUA (see below). Data obtained from these assays will provide the basis for optimizing a mathematical model (IAX Systems biology model) of the signaling map of CXCR4 and ACKR3 consisting of Ordinary Differential Equations (ODE). Such models will then help to gain a deeper understanding of how ligands activate and regulate these receptors and will be crucial for designing novel drugs targeting these important receptors.

Planned secondments:

University of Nottingham – Generate data using genetically-encoded biosensors for ERK, PKC (coll ESR11) and integrate into IAX Systems biology model  

Vrije Universiteit Amsterdam – Integrate data derived with phospho/dimer mutant CRISPR/CAS cell lines (ESR10) into IAX Systems biology model

 

II – Requirement candidate:

Required diploma: MSc degree in a relevant biological area, as well as above-basic experience in programming. Candidates with degrees related to systems biology are particularly encouraged to apply.

Required expertise: For biology majors: mammalian cell culture. For computational majors: strong programming skills (ideally R and/or Matlab), formal training in statistics and numerical simulations of ODEs. 

Recommended expertise: Biology majors: GPCR biology, Signal Transduction. Computational majors: modelling of dynamic biochemical networks using time-resolved data, numerical optimization techniques.

Key publications:

  1. Roth S., Kholodenko BN, Smit MJ, Bruggeman FJ (2015). G Protein-Coupled Receptor Signaling Networks from a Systems Perspective. Mol Pharmacol., 88(3): 604-16.
  2. Roth S., Bruggeman FJ (2014). A conformation-equilibrium model captures ligand-ligand interactions and ligand-baised signaling by G-protein coupled receptors. The FEBS Journal, 281(20): 4659-4671.
  3. Rizk A., Paul G., Incardona P., Bugarski M., Mansouri M., Niemann A., Ziegler U., Berger P;, Sbalzarini I.F. (2014). Segmentation and quantification of subcellular structures in fluorescence microscopy images using Squassh. Nature Protocols, 9(3), 586–596.
  4. Roed S.N., Wismann P., Underwood C.R., Kulahin N., Iversen H., Cappelen K.A., Schäffer L., Lehtonen J., Hecksher-Soerensen J., Secher A., Mathiesen J.M., Bräuner-Osborne H., Whistler J.L., Knudsen S.M., Waldhoer M. (2014). Real-time trafficking and signaling of the glucagon-like peptide-1 receptor. Mol Cell Endocrinol., 8.

For more information:
Dr. Maria Waldhoer – waldhoer@interaxbiotech.com

 

Application:

Please send your application to recruiting@interaxbiotech.com   

Include in heading – ONCORNET2.0 application + ESR#

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Contact details

Please contact us at:
info@oncornet.eu

ONCORNET Coordinator
VU University Amsterdam
The Netherlands