Dr J-M Schwartz, Dr C Francavilla
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Receptor tyrosine kinases (RTKs) enable cells to respond to the extracellular environment and to decide whether to grow, differentiate or die. Growth factors binding to and activating RTKs control differentiation, proliferation and migration by initiating intracellular signaling cascades. However, how different ligands binding to the same receptor orchestrate the activation of specific signaling pathways and specific outputs (i.e. proliferation vs migration) is not understood.
Mass Spectrometry (MS)-based quantitative phosphoproteomics is a powerful technology to monitor changes in the activation of signaling pathways by measuring phosphorylated peptides. Focusing on the family of Fibroblast Growth Factor Receptors (FGFRs), which plays major roles during embryonic development and breast cancer1,2, we have demonstrated that signals controlling cell proliferation and cell migration are encoded by the ligands binding to FGFRs. By combining quantitative phosphoproteomics with state-of-the-art systems biology analysis, mathematical modelling and cellular assays, this project will test whether molecular determinants of cell proliferation and migration can be predicted in silico. Specifically, we will:
1. Build a mathematical model from existing phosphoproteomics data collected in human epithelial cells upon stimulation with several FGFR ligands. We will use dynamic correlation analysis in order to reconstruct a network of functional interactions between proteins, and a range of network analysis methods to identify groups of functionally related proteins. We will also develop new methods to visualize networks of phosphorylated proteins.
2. Investigate the validity of the mathematical model by generating new quantitative phosphoproteomics datasets in cells stimulated with other ligand/receptor pairs and in breast cancer cells. We will search for common signaling modules predictive of cellular outcomes (proliferation and migration).
3. Verify the predictive potential of the mathematical model by testing the role of the molecular players identified above in cell proliferation and cell migration assays. We will use two and three dimension epithelial cell cultures.
By combining cutting-edge -omics technology, mathematical modelling and functional assays, the recipient of this studentship will make a significant contribution to our understanding of how cellular decisions are generated and regulated.
http://www.bioinf.manchester.ac.uk/schwartz/
http://www.manchester.ac.uk/research/chiara.francavilla/
Funding Notes
This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form, full details on how to apply can be found on the BBSRC DTP website http://www.dtpstudentships.manchester.ac.uk/
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
1. Dorey, K. & Amaya, E. FGF signalling: diverse roles during early vertebrate embryogenesis. Development 137, 3731-3742 (2010).
2. Fearon, A.E., Gould, C.R. & Grose, R.P. FGFR signalling in women's cancers. The international journal of biochemistry & cell biology 45, 2832-2842 (2013).
3. Narushima Y, Kozuka-Hata H, Tsumoto K, Inoue JI, Oyama M. Quantitative phosphoproteomics-based molecular network description for high-resolution kinase-substrate interactome analysis. Bioinformatics 32, 2083-2088 (2016).
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