MRC DiMeN Doctoral Training Partnership: The role of phosphodiesterases (PDEs) in atrial IP3 signaling: Exploring the potential of utilizing PDEs as therapies for atrial fibrillation

Our project is aligned with MRC and DiMeN Strategy - to tackle major health problems and improve human health. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia (incidence 1-2%). Age-related increases in the risk for AF contribute to 14% of strokes in the UK, as well as heart failure and dementia, leading to a substantial healthcare burden. Some therapeutic drugs/interventions are not always 100% effective and have some associated morbidity/mortality issues. Because traditional antiarrhythmic medications lack particular molecular targets, understanding the molecular aetiology of AF is essential.

Inositol 1,4,5-trisphosphate (IP₃), a Ca²⁺ mobilising second messenger, regulates Ca²⁺ release from the sarcoplasmic reticulum via IP₃ receptors (IP₃R). IP₃R expression is higher in atria compared to ventricles and upregulated in AF. IP₃ signalling can be pro-arrhythmic, causing spontaneous Ca²⁺ and electrical activity in atria. IP₃R inhibition protects against AF in animal models. The IP₃ pathway has therefore been proposed as a potential atrial-specific target for the treatment of AF.

We recently found that atrial IP₃R Ca²⁺ release activates Ca²⁺ sensitive adenylyl cyclases resulting in generation of cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA). Localisation of cAMP and PKA signals is maintained by phosphodiesterases (PDEs). Additionally, cAMP and PKA regulate the response of IP₃R to IP₃. Altering PDE activity could provide a mechanism for modulating atrial IP₃ signalling.

This project will investigate the therapeutic potential of atrial IP₃ signalling and PDEs in regulating atrial function. The investigations will focus on identifying cellular mechanisms in animal, human tissue, human cell models (hiPSC-derived cardiomyocytes). Structure-functional studies will be performed using state-of-the-art imaging modalities (super resolution, confocal microscopy, Microelectrode arrays, MRI) at the Centre for Cellular Imaging. Transcriptomics and proteomics will also be explored at the genomics and proteomics facilities in Liverpool. Additionally, our collaborator from Oxford will consult on MRI and human-based cell stem cell experimentation, matrices and scaffolds including methods related to loading scaffolds with cells.

Novelty: (i) We will be able to comprehend the spatial localization and function of atrial PDEs and IP3Rs in persistent AF for the first time. (ii) These investigations will provide light on whether elevated IP3R expression in AF results in elevated IP3 signalling in human tissue and offer potential treatment options that involve modifying IP3R expression or signalling in AF.

Training: The supervisory team consisting of primary, secondary and tertiary supervisors bring added value by encompassing different-departments, experience, multi-disciplinary scientists with strategically aligned skills for delivering a bench to bedside project. The Primary-supervisor is an experienced scientist in cardiac imaging and proteomics methods. Structural studies for model-validation and functional imaging using microscopes available at CCI. The Secondary-supervisor is a world leading clinician scientist in the field of AF. For MRI and NMR spectroscopy, Tertiary-Supervisor will provide the student with training and supervision. Students will receive project specific training from the Shared Facility-Centers, training through PGR Training catalogue in (not limited to) statistical data analysis, data preservation, Good Laboratory Practice, Ethics in Research. In addition the student will receive training via the Industrial partner Axol Bioscience with research expertise in Cardiovascular diseases. Specifically designed University wide training is available for all doctoral/PGR students.

https://www.liverpool.ac.uk/people/rebecca-ann-burton

https://www.liverpool.ac.uk/people/gregory-lip

https://www.liverpool.ac.uk/people/harish-poptani

iCASE industrial partner web link: http://www.axolbio.com

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/