Supervisors:
Dr James Hislop - University of Aberdeen, Institute of Medical Sciences - [Email Address Removed]
Professor Gopal Sapkota - Dundee, School of Life Sciences, MRC PPU - [Email Address Removed]
Project Description for Advert (max 500 words). This will be the text that is advertised to prospective students:
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of signalling proteins in the body and are essential for regulating almost every physiological process. GPCRs can function in a dynamic range of conditions and are able to adapt to the demands of the environment, reducing the size of response to prevent overstimulation and increasing signal size in low activity conditions, maintaining homeostasis. This dynamic regulation is vital, as any disruption to this process can lead to serious health consequences. One such regulatory mechanism is that cells can acutely change how many receptors are expressed at any given time by controlling the synthesis of new receptors and the destruction of existing ones, a mechanism that if disrupted, underlies disease states. One example of this are the GPCRs that respond to acetylcholine – Muscarinic receptors, which are lost over the course of our lifetime, and are in part responsible for the cognitive decline and loss of memory associated with old age. Further, the same receptor loss is seen in disease states such as schizophrenia and addiction (1). It is therefore vital to understand how this regulation of receptor number is controlled and the impact this has on cellular physiology.
This studentship will combine the expertise in GPCR pharmacology of the Hislop lab with the protein engineering of the Sapkota lab to identify critical regulatory checkpoints in muscarinic receptor regulation and function to identify novel intervention strategies for future therapeutic development. As a starting point, we will investigate the role of the ubiquitin-lysosome system in controlling downregulation of muscarinic receptors. Direct ubiquitination is implicated in GPCR downregulation and is regulated by a balance of activities of ubiquitin ligases and deubiquitinating enzymes (2). Using molecular cloning, mutagenesis confocal microscopy and biochemical analysis, we will determine the role of ubiquitination in the regulation of muscarinic receptor levels. We will also utilise novel techniques such as proximity labelling (APEX2/TurboID combined with mass spectrometry to identify the specific protein-protein interactions responsible. We will go on to use novel protein engineering technologies developed by the Sapkota lab (3) to control the expression level of muscarinic receptors. This technology uses engineered protein connectivity to specifically target proteins for ubiquitination on demand to drive downregulation. This project will utilise this technology to downregulate the muscarinic receptors and allow us to determine exactly how this dynamic process influences receptor signalling both acutely and at the transcriptional level.
This studentship will use a diverse array of modern scientific techniques including state of the art protein engineering combined with biochemical analysis and fluorescent imaging techniques to fully determine how muscarinic receptors are regulated and identifying potential targets for therapeutic intervention.
Application Procedure:
Please visit this page for full application information: http://www.eastscotbiodtp.ac.uk/how-apply-0
Please send your completed EASTBIO application form, along with academic transcripts to Alison Innes at [Email Address Removed]
Two references should be provided by the deadline using the EASTBIO reference form.
Please advise your referees to return the reference form to [Email Address Removed]
Unfortunately due to workload constraints, we cannot consider incomplete applications
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