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In-depth analysis of the gating of arrhythmia-linked mutant cardiac ryanodine receptor Ca2+-release channels

  • Full or part time
  • Application Deadline
    Friday, January 31, 2020
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

The cardiac ryanodine receptor (RyR2) is responsible for releasing Ca2+ from intracellular stores during the process of excitation-contraction coupling, its normal function contributing to the rhythmic progression of each cardiac cycle. Mutation of the gene encoding this Ca2+ release channel is known to result in life-threatening arrhythmia. Many mechanisms have been proposed to explain mutant RyR2 channel dysfunction in the arrhythmia syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT). Ca2+ is the primary activating ligand of RyR2, so it’s unsurprising that defective regulation of the channel by Ca2+ has been implicated in the pathogenesis of CPVT. Other mechanisms are thought to involve alteration of response to post-translational modification, lipid environment or accessory protein binding. Single channel recording allows us to analyse the gating behaviour (i.e. patterns of opening and closing) of individual RyR2 channels in a minimal environment in the presence/absence of agonists/modifiers of activity, allowing the influence of each to be assessed. We are able to build gating schemes that describe the detailed mechanism by which Ca2+ regulates the behaviour of the wild type channel and hope to extend this mechanistic description to interpret mutation-linked RyR2 dysfunction in response to the various agents involved in pathogenesis. Recombinant expression in a mammalian cell line allows us to engineer point mutations and purify single channels to use in this system. Preliminary studies indicate that some mutations cause inappropriate channel opening in the absence of activating ligands whereas others require activation to reveal dysfunction and this may impact the efficacy of RyR2-targeted therapeutic agents. Detailed analysis of single channel kinetics will be used to interpret this functional heterogeneity and the implications of gating changes on channel-targeted pharmacology.

How to Apply

Applicants should apply to the Doctor of Philosophy in Pharmacy and Pharmaceutical Sciences with a start date of April 2020.
In the research proposal section of your application, please specify the project title and supervisors of this project and copy the project description in the text box provided. In the funding section, please select ’I will be applying for a scholarship/grant’ and specify that you are applying for advertised funding from In-depth analysis of the gating of arrhythmia-linked mutant cardiac ryanodine receptor Ca2+-release channels.

Funding Notes

100% School Funded Project for EU/UK Students, will cover fees and provide a stipend of £15,009 per annum

Related Subjects

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