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Elphinstone Scholarship - Novel drug targets for pulmonary arterial hypertension: dissecting the phosphodiesterase 1 signalsome


   School of Medicine, Medical Sciences & Nutrition

  ,  Thursday, July 29, 2021  Competition Funded PhD Project (Students Worldwide)

Aberdeen United Kingdom Molecular Biology Pharmacology Physiology Synthetic Chemistry

About the Project

Pulmonary arterial hypertension (PH), which is high blood pressure in the lung, is characterized by increased pulmonary artery smooth muscle cells (PASMC) in the walls of the blood vessels, raised pulmonary vascular resistance, right ventricular failure and premature death. Pulmonary arterial hypertension (PAH), which is a specific type of PH where the disease originates in the pulmonary arteries themselves, has a poor prognosis and treatments costs up to £300,000/year/patient: new treatments of PAH are an important unmet medical need.

The ubiquitously expressed second messenger, cyclic AMP (cAMP), plays a fundamental role in controlling cellular responses that regulate physiological processes throughout the body. Compartmentalization of cAMP is key in the spatio-temporal control of cAMP dynamics that determines its function in cells (1). 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 interactions and the design of novel peptide disrupters, has uncovered the role of such complexes in cell function and represent exciting novel therapeutics (1). Peptide disrupters have higher target specificity compared to traditional small molecules (2).

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 associated with pulmonary arterial hypertension (PAH, 3). 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, 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, 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, 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 PDE1 signalsomes and uncover novel targets and peptide therapeutics for PAH.

APPLICATION PROCEDURE:

Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.


Funding Notes

This project is funded by a University of Aberdeen Elphinstone Scholarship. An Elphinstone Scholarship covers the cost of tuition fees only, whether home, EU or overseas. Please note, no stipend is available for this project.
Candidates should have (or expect to achieve) a First Class Honours undergraduate degree (or equivalent) in a relevant subject, plus a Masters degree awarded with Commendation/Distinction.

References

1. Blair, CM and Baillie, GS. Reshaping cAMP nanodomains through targeted disruption of compartmentalised PDE signalosomes. Biochemical Society Transactions, 47, 1405-1414, 2019
2. Idress M, Milne BF, Thompson GS, Trembleau L, Jaspars M and Houssen, WE. Structure‐based design, synthesis and bioactivity of a anti‐TNFα cyclopeptide. Molecules, 25, 922. 2020
3. Murray F, Patel H, Suda R, Zhang S, Thistlethwaite P, Yuan J, Insel P. Expression and activity of cAMP phosphodiesterase isoforms in PASMC from patients with pulmonary hypertension: role for PDE1. Am J Physiol Lung Cell Mol Physiol. 292:L294-303. 2007

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