RNA-binding proteins (RBPs) interact with RNA molecules and help determine their fate. Such interactions have essential roles across cell biology, whilst perturbed interactions contribute to several diseases1. Of relevance to this PhD, several RBPs are mutated in genetically inherited forms of the devastating motor neuron disease, amyotrophic lateral sclerosis (ALS).
In this PhD project the student will learn both experimental and computational approaches necessary to study and comprehensively model RBP target networks. Specifically, the functional genomics approach of iCLIP will be used to determine interactions of multiple ALS-associated RBPs with RNA1, RNA-sequencing will be used to determine transcriptome-wide consequences following silencing of these same RBPs, and computational analysis will be used to predict their RBP binding motif sites on a genome-wide scale. Last, the student will learn to computationally model RBP activity as a Bayesian network by integrating all these complementary, yet individually incomplete, datasets2. The powerful models that are generated by the student will be the first of their kind for ALS. They will be used to characterise the functional target networks of multiple ALS-associated RBPs and understand the way in which they recognise their interacting RNAs. Cell-type specific RNA targets will be identified with expected relevance to the progression of ALS, and these will be validated with standard molecular biology techniques (e.g. qPCR, western blotting, cell-based assays) in human pluripotent stem cell models that are differentiated into motor neurons and/or astrocytes3 by the student during their final year. Finally, the student will meta-analyse models of multiple distinct RBPs associated with ALS to reveal aspects of mechanistic convergence across distinct disease cohorts.
The PhD will be supervised by Dr Sibley (experimental / computational) and Professor Grima (computational) who have extensive expertise covering all project methodology. Alongside exposure to more standard molecular biology methods, the student will develop unique expertise in a range of complementary and state-of-the-art experimental and computational approaches that are becoming increasingly important in life sciences research. The student will integrate into the University of Edinburgh’s globally recognised community of leading RNA biologists, and benefit from excellent graduate training opportunities that are on offer at the School of Biology.
Sibley lab: www.thesibleylab.com
Grima lab: http://grimagroup.bio.ed.ac.uk
School of Biology: https://www.ed.ac.uk/biology
Approximately 80% of the supervision will be from Dr Sibley, and 20% from Professor Grima. The student will be based in the lab of Dr Sibley at 1 George Square, Edinburgh. The lab will comprise ~4 staff and include multiple post-doctoral research associate’s expert in RNA biology. The lab’s funding for ALS research comes from the Wellcome Trust and Royal Society. There will be opportunity to support undergraduate research projects during later stages of the project.
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If you would like us to consider you for one of our scholarships you must apply by 5 January 2020 at the latest.
1 Modic M, Ule J, Sibley CR. CLIPing the brain: studies of protein-RNA interactions important for neurodegenerative disorders. Mol Cell Neurosci. 2013 Sep;56:429-35.
2 Zhang C, Frias MA, Mele A, Ruggiu M, Eom T, Marney CB, Wang H, Licatalosi DD, Fak JJ, Darnell RB. Integrative modeling defines the Nova splicing-regulatory network and its combinatorial controls. Science. 2010 Jul 23;329(5990):439-43.
3 Hall CE, Yao Z, Choi M, Tyzack GE, Serio A, Luisier R, Harley J, Preza E, Arber C, Crisp SJ, Watson PMD, Kullmann DM, Abramov AY, Wray S, Burley R, Loh SHY, Martins LM, Stevens MM, Luscombe NM, Sibley CR, Lakatos A, Ule J, Gandhi S, Patani R. Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS. Cell Rep. 2017 May 30;19(9):1739-1749.
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