Supervisors:
Dr Fiona Murray - University of Aberdeen, Institute of Medical Sciences, Systems Physiology - [Email Address Removed]
Dr Wael Houssen - University of Aberdeen, Institute of Medical Sciences, Infection and Immunity - [Email Address Removed]
Professor George Baillie - University of Glasgow, Institute of Cardiovascular & Medical Sciences - [Email Address Removed]
The ubiquitously expressed second messenger, cyclic AMP (cAMP), plays a fundamental role in controlling cellular responses that regulate a wide number of physiological processes throughout the body. Compartmentalization of cAMP is key in the spatio-temporal control of cAMP dynamics that determines its function in cells. Phosphodiesterase (PDEs), which hydrolyse cAMP, underpin compartmentalization of cAMP by forming specific protein complexes (signalsomes) that restrict cAMP within subcellular compartments. Such protein complexes, which also include membrane-bound proteins (e.g. G protein-coupled receptors or adenylyl cyclases), scaffolding proteins (e.g. A kinase anchoring proteins) and downstream mediators (e.g. protein kinase A) permits the integration of cAMP signalling with other signalling pathways. Identification of PDE signalosomes has uncovered PDE-specific protein complexes, many of which are implicated in heart failure, cancer and cognitive decline. Mapping of PDE–protein interfaces and the rational design of novel peptide disrupters has uncovered the role of such complexes in cell function and represent exciting novel therapeutic targets. Peptide disrupters have higher target specificity compared to traditional small molecules.
We have shown a specific PDE family member, PDE1C, plays a pivotal role in shaping cAMP gradients in pulmonary artery smooth muscle cells (PASMCs) and its increased expression and activity accounts for lower cAMP and increased PASMC proliferation in pulmonary arterial hypertension (PAH)1. PDE1C limits the efficacy of prostacyclin analogues, which are currently clinically approved for PAH, by interacting with the prostacyclin (IP) receptor and enhancing its degradation. Using a variety of molecular and biochemical approaches together with ‘peptide chip’ technology (Professor Baillie), this project aims to define the interacting proteins, subcellular localisation and function of this exciting newly discovered PDE1C/IP signalsome. We will develop novel peptide disruptors, including cyclic peptides (Dr Houssen) using synthetic biology and chemistry, to elucidate the functional significance of the PDE1C/IP complex in PASMC and its role in PAH. This proposed PhD project brings together areas of expertise in pulmonary physiology, pharmacology, biochemistry, synthetic biology and chemistry from the University of Aberdeen and University of Glasgow, which will offer an optimal training environment and provide the student with a set of highly desirable skills. It is expected that completion of the aims will advance our understanding of the cellular function of PDE1C/IP signalosomes and uncover novel peptide therapeutics for diseases.
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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