Regulated insulin secretion from pancreatic beta cells is essential for metabolic homeostasis. Beta cell dysfunction/failure is a hallmark of both major forms of diabetes1, resulting in hyperglycaemia and many associated complications. Diabetes affects 463m people worldwide (expected to rise to 700m by 2045; www.idf.org) and is a major burden on quality of life, productivity and healthcare expenditure (~10% of the NHS budget).
MRC Doctoral Training Programme
Endothelial dysfunction is prevalent in obese and elderly individual and in patients who have diabetes.
Behavioural neuroscience using rodent models is an established and essential area of biomedical research, but one which can be high cost in terms of time, finances and animal welfare. At the forefront of modern animal research is the need to address the principles of the 3Rs- Replacement, Reduction and Refinement.
The eIF2a kinase GCN2 is an amino acid starvation sensing protein, and is a therapeutic target in cancer, diabetes, and myocardial infarction. However, its structure and mechanism of activation are poorly understood1. When proteins are activated, they often become more flexible as autoinhibitory intramolecular interactions are broken, making structural characterisation more difficult. In this project both two complementary tools – hydrogen deuterium exchange mass spectrometry (HDX-MS) and nanobodies will be used together to facilitate insight into GCN2 activation.
The epigenetic mark of DNA methylation is established by DNMT (DNA methyltransferase) enzymes and has been shown to correlate with transcriptional states and influence cell identity and tumorigenesis in mammalian cells.
Protein O-GlcNAcylation is an essential posttranslational modification of Ser/Thr residues on nucleocytoplasmic proteins with N-acetylglucosamine (GlcNAc). It is regulated by two opposing enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). OGT catalyses O-GlcNAcylation and possesses a catalytic domain and N-terminal tetratricopeptide repeats (TPRs) that mediate substrate recognition.
With ageing of the population, the prevalence of neurodegenerative disorders and the associated socioeconomic burden have dramatically increased. New therapeutic and prevention strategies are urgently needed. The prevalence of Parkinson's disease (PD) is projected to double by 2030, and there are no effective disease-modifying therapies to date1.
Protein O-GlcNAcylation is an essential posttranslational modification of Ser/Thr residues on nucleocytoplasmic proteins with N-acetylglucosamine (GlcNAc). It is regulated by two opposing enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) (Fig. 1). OGT catalyses O-GlcNAcylation and possesses a catalytic domain and N-terminal tetratricopeptide repeats (TPRs) that mediate substrate recognition. Ogt is X-linked in vertebrates and is required for mouse embryogenesis.
This PhD project will combine mathematical modelling and experimental approaches in order to understand the spatiotemporal dynamics that regulate asymmetric cell division. Asymmetric cell division is a fundamental process that generates cellular diversity. Moreover, stem cells in higher organisms can polarise and segregate evolutionarily conserved fate determinants unequally to the resulting daughter cells that then undergo different developmental programs.
The Findlay lab employs cutting-edge technologies to unravel Embryonic Stem (ES) cell signalling networks, culminating in our discovery of the ERK5 pathway as an exciting new regulator of ES cell pluripotency (Williams et al, Cell Reports 2016; Brown* Williams* et al, in preparation). In order to uncover functions of ERK5 in ES cells, this project will deploy global proteomic and phosphoproteomic profiling.