MSc by Research: How does Dysregulated Protein Kinase Signalling Cause Human Neurodevelopmental Disorders?

About the Project

The overarching goal of this project is to identify and characterise protein kinase signalling pathways that are disrupted in human neurodevelopmental disorders. This research will uncover new therapeutic targets and avenues that might be used in treatment of patients these debilitating 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 adult tissues and organ, such as the brain. As a result, protein kinase signalling pathways are frequently dysregulated in human neurodevelopmental 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. However, beyond several notable examples, protein kinase pathways, regulatory mechanisms and molecular functions that control human neurodevelopmental 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 gene expression programmes required for neurodevelopment, whilst genes encoding SRPK-RNF12 pathway components are mutated in a series of related human neurodevelopmental disorders including Tonne-Kalscheuer syndrome (TOKAS). These data suggest that the SRPK pathway plays a key role in neurodevelopmental regulation, and that dysregulated SRPK signalling may underpin human neurodevelopmental disorders.

The goal of this project is to identify novel SRPK substrates that are relevant for human neurodevelopment by state-of-the-art global phosphoprotemic profiling of human induced pluripotent stem cell (hiPSC)-derived neural cell types. The student will explore mechanisms by which SRPK phosphorylation regulates molecular functions of key substrates, and how newly identified SRPK signalling pathways control downstream neurodevelopmental processes using hiPSC models. Finally, they will determine whether and how the SRPK signalling pathways are disrupted in patients with neurodevelopmental disorders.

This project offers a unique opportunity to illuminate new molecular mechanisms underpinning human neurodevelopment that are disrupted in disease.

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.

Please see our website for further details on the programme and how to apply:

Life Sciences MSc by Research MSc by Research (Postgraduate) : Study : University of Dundee