China Scholarship Council: How does Dysregulated Protein Kinase Signalling Cause Human Developmental Disorders?


   School of Life Sciences

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  Dr Greg Findlay, Dr M Stavridis  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

The overarching goal of our research is to identify and characterise protein kinase signalling pathways that are disrupted in human developmental disorders. 

Protein kinases function as reversible switches in signal transduction and as such are fundamental regulators of all cellular processes. A major role for protein kinases during human development is controlling differentiation of pluripotent stem cells (PSCs) into adult tissues, such as neurons, cardiomyocytes and hepatocytes. As a result, protein kinase signalling pathways are frequently dysregulated in human developmental disorders. Because protein kinase activity can be specifically and reversibly manipulated using chemical tools for therapeutics and tissue engineering, there is a pressing need to identify relevant protein kinase circuits in PSCs. However, beyond several notable examples, protein kinase pathways, regulatory mechanisms and molecular functions that control developmental processes remain poorly understood.  

Ser-Arg Protein Kinase (SRPK) has been known for many years to phosphorylate splicing factors to promote spliceosome assembly and mRNA splicing. However, we recently showed SRPK has acquired splicing independent functions during human development. SRPK phosphorylates the E3 ubiquitin ligase RNF12/RLIM to pattern genetic programmes required for development, whilst SRPK-RNF12 pathway components are disrupted in a series of related developmental disorders. These data suggest that SRPK signalling plays a key role in stem cell regulation, and that dysregulated SRPK signalling may underpin human developmental disorders. 

The goal of this project is to identify novel developmental SRPK substrates by state-of-the-art global phosphoproteomic profiling in PSCs. The student will explore mechanisms by which SRPK phosphorylation regulates molecular functions of key substrates, and how newly identified SRPK signalling pathways control downstream biological processes in PSCs and differentiating tissues. Finally, they will determine whether and how the SRPK signalling pathways are disrupted in patients will developmental disorders. This project offers a unique opportunity to illuminate new molecular mechanisms underpinning PSC regulation and their dysregulation in human disease. 

Biological Sciences (4) Medicine (26)

Funding Notes

In order to be eligible for these awards applicants must:
Be a Chinese national
Meet the requirements of the CSC – please see their website
Hold an unconditional offer to study for a PhD at the University of Dundee and meet our English language requirements
Have completed a bachelors or masters degree before the agreed start of PhD study.
Already have an IELTS score of 6.5 at time of applying
For further information on the CSC programme please visit https://www.dundee.ac.uk/phds/funding/china-scholarship-council-csc-programme and apply by completing our application form - https://dundee.onlinesurveys.ac.uk/csc-programme-2024-entry

References

Selected recent work from the lab can be found in the following references:
Bustos, F., Segarra-Fas, A., Nardocci, G., Cassidy, A., Antico, O., Brandenburg, L., Macartney, T., Toth, R., Hastie, C.J., Gourlay, R., Vargese, J., Soares, R., Montecino, M. and Findlay, G.M. (2020) Functional diversification of SRSF protein kinase to control ubiquitin-dependent neurodevelopmental signalling. Dev Cell. 55(5):629-647
Fernandez-Alonso, R., Bustos, F., Budzyk, M., Kumar, P., Helbig, A.O., Hukelmann, J., Lamond, A.I., Lanner, F., Zhou, H., Petsalaki, E. and Findlay, G.M. (2020) Phosphoproteomics Identifies a Bimodal EPHA2 Receptor Switch that Promotes Embryonic Stem Cell Differentiation. Nat Commun. 11(1): 1357. doi: 10.1038/s41467-020-15173-4
Bustos, F.*, Segarra-Fas, A.*, Chaugule, V.K., Brandenburg, L., Branigan, E., Toth, R., Macartney, T., Knebel, A., Hay, R.T., Walden, H. and Findlay, G.M. (2018) RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation. Cell Rep. 23(6): 1599-1611

Where will I study?

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