Understanding why cardiovascular complications are the number one cause of death in patients with End-Stage Kidney Disease

Description

Proteins are extensively regulated by dynamic, often reversible post-translational modifications (PTMs). This process allows cells to respond rapidly to environmental factors, be that e.g. growth factors, stressors, or contact adhesion with other cells, ultimately allowing cells to adapt. Importantly, protein modifications have been shown to be differentially regulated in numerous diseases, including cancer, serving as both markers of disease and facilitating treatment stratification.

Protein phosphorylation is a key PTM that is known to be differentially affected during cancer, and inhibitors of enzymes that regulate phosphorylation are often used as clinical therapeutics. However, studies to date focus on phosphorylation of serine, threonine, and tyrosine residues. Having recently demonstrated that non-canonical phosphorylation of 6 other amino acids is extensive in human cells, we have an interest exploring the dynamics and regulation of these novel phosphorylation events in cell signalling and as drivers/markers for cancer.

Specific objectives:

1. Apply novel quantitative mass spectrometry-based analytical pipelines to explore and quantify atypical phosphorylation in U2OS osteosarcoma cells exposed to cellular stimuli/stressors/inhibitors, including regulators of protein kinase networks and mitochondrial dysfunction.
2. Exploit a variety of computational strategies e.g. residue conservation, motif discovery, pathway analysis, mining protein-protein interaction database, to cross-correlate PTM types and sites and predict interplay and regulatory mechanisms.
3. Undertake cell and tissue-based studies to understand the mechanisms of regulation of key modified targets and potential use as clinical markers.

Outcomes:

• Understanding of the extent of phosphorylation on human proteins, and their contextual information, with a focus on atypical phosphorylation
• Experience in presentation of findings at appropriate analytical/technology and cell signalling meetings
• Training in fundamental MS and computational biology, making future employability high
• Collaboration with clinical academics

The project is suited to a student with at least a good B.Sc. Upper Second in e.g. Biochemistry, Chemistry or related disciplines. 

How to apply

Please contact the project primary supervisor directly to apply to this project, including your CV and covering letter. No other application formats will be accepted.

Applications will be reviewed until a suitable candidate is appointed.