Modifying protein clustering as a novel repair strategy in heart failure. Physics, PhD (GW4 BioMed MRC DTP) Ref: 3226

About the award

Supervisors

Lead Supervisor:  
Professor Christian Soeller, Department of Physics, Living Systems Institute, University of Exeter 

Additional Supervisors: 
Professor Derek Blake, University of Cardiff 
Dr Akshay Bhinge, University of Exeter

Project Details:

Heart failure (HF) is one of the leading causes of death worldwide and has reached epidemic proportions in most industrialized nations. Despite major improvements in the treatment and management of the disease, the prognosis for patients with heart failure remains poor, in part due to irreparable damage to cardiac tissue.   

Cardiac muscle contraction is enabled by transient increases in cellular calcium levels termed calcium transients. Weakened calcium transients mediated by ryanodine receptors (RyRs), which are intracellular calcium channels, is one of the major pathological features of HF. Recently it has been recognized that heart cell function can be greatly affected by modulation of receptor clustering. Receptor clustering refers to the close grouping of RyRs within intracellular store membranes so that adjacent receptors are only few tens of nanometers apart. In heart cells RyR clustering is essential for physiological contraction.   

In pathological conditions, smaller and less dense RyR clusters lead to an increased loss of calcium from intracellular stores and decrease the ability to release calcium, weakening contraction. We hypothesize that cellular function can be restored by enhancing receptor clustering thus facilitating the repair of damaged cardiomyocytes . We will study this by using a novel regulator of RyR clustering that we recently identified, the myospryn family. To investigate this novel repair approach we will use stem cell derived cardiac myocytes (iPSC-CMs). iPSC-CMs provide both a readily manipulatable cellular system and have the potential to provide an alternative to conventional cell transplantation therapies that have shown little clinical benefit to date.   

By comparison to other protein modifications, where well-developed biochemical assays are available, we are currently lacking tools to quantitatively study protein clustering, e.g. of RyRs, because such approaches require in situ cellular measurements with molecular resolution. This project will close this gap by refining our recently introduced molecule-counting, fully quantitative super-resolution fluorescence imaging approaches to provide robust and routine in situ molecular clustering assays. We will apply this improved methodology to measure RyR cluster properties and relate this to functional phenotypes, quantified as the ability to release calcium from intracellular stores. Our expectation is that increasing RyR clustering will increase the cellular ability to release calcium, which makes the cell contract strongly, and thus restore function.   

This project will firmly establish quantitative and robust protein clustering assays and explore protein clustering as a novel therapeutic target. The new in-situ assays will be applicable to protein targets in a wide variety of cell systems.


Funding

This studentship is funded through GW4 BioMed MRC Doctoral Training Partnership. It consists of full UK/EU tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£14,777 for 2018/19, updated each year) for 3.5 years.

For further information relating to the funding please see the main MRC GW4 BioMed website

This project is in competition with 69 other projects; up to 18 studentships will be available


Eligibility and Residency Requirements
To be eligible for a full award (fees and stipend) from a Research Council, a UK or EU student must have no restrictions on how long they can stay in the UK and have been ordinarily resident in the UK for at least 3 years prior to the start of the studentship.

An EU student who has not been resident in the UK for at least 3 years prior to the start of the studentship is generally eligible for a fees-only award from the Research Council: to be eligible for a fees-only award, a student must be ordinarily resident in a member state of the EU; in the same way as UK students must be ordinarily resident in the UK.

For our regular recruiting round, the Doctoral Training Partnership has additional funding from the partner universities to support a limited number of EU students who do not meet the UK residency requirements, so long as they meet the criteria for a fees-only award: these studentship will therefore be fully funded (fees and stipend).

For full details on eligibility, please refer to the MRC GW4 BioMed website

Students with 'International' status are unfortunately not eligible to apply.


Data Protection
If you are applying for a place on a collaborative programme of doctoral training provided by Cardiff University and other universities, research organisations and/or partners please be aware that your personal data will be used and disclosed for the purposes set out below.

Your personal data will always be processed in accordance with the  General Data Protection Regulations of 2018. Cardiff University (“University”) will remain a data controller for the personal data it holds, and other universities, research organisations and/or partners (“HEIs”) may also become data controllers for the relevant personal data they receive as a result of their participation in the collaborative programme of doctoral training (“Programme”).

For further information regarding data protection for the Application Process and if you become a student on one of the Programmes please click here


Further Information
For an overview of the MRC GW4 BioMed progamme, please see the website www.gw4biomed.ac.uk

Entry requirements

Academic criteria
In addition to those with traditional biomedical or psychology backgrounds, the DTP welcomes students from non-medical backgrounds, especially in areas of computing, mathematics and the physical sciences, and can fund additional training, including Masters to assist discipline conversion. Applicants for a studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an area appropriate to the skills requirements of the project. Applicants with a Lower Second Class degree will be considered if they also have a Master’s degree or have significant relevant non-academic experience.

English requirements
If English is not your first language you will need to have achieved at least 6.5 in IELTS (and no less than 6.5 in any section) by the start of the programme.

How to apply

Applications Open on 24 September and close at 17:00 on Friday 23 November 2018

You will need to complete an application to the GW4 BioMed MRC DTP for an 'offer of funding'

Applying for an 'offer of funding'

Please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-dtp-student-2019 by 5pm Friday 23 November 2018. 

The Research Theme Panels will complete the shortlisting and inform applicants by 18th December 2018.  If you are shortlisted you will need to:

  • contact your chosen supervisor(s) to arrange an informal meeting (which can be in person, by telephone or by Skype) with the Lead supervisor of the projects in which you are interested by, 14 January 2019.  Please note that interview expenses will not be available for candidates to attend these meetings.
  • Attend a formal interview, with a panel of four academics which will take place in Cardiff toward the end of January. 

For further details of the application process please see the following web page www.gw4biomed.ac.uk/doctoral-students/

You do NOT need to apply to the University of Exeter at this stage - only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Exeter.

Summary

Application deadline:23rd November 2018
Value:Stipend matching UK Research Council National Minimum (£14,777 p.a. for 2018/19, updated each year) plus UK/EU tuition fees
Duration of award:per year
Contact: PGR Enquiries pgrenquiries@exeter.ac.uk