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The role of the CGRP family of peptides in the heart; new therapies for heart disease?

College of Health and Life Sciences

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Prof D Poyner No more applications being accepted Funded PhD Project (UK Students Only)
Birmingham United Kingdom Bioinformatics Genetics Molecular Biology

About the Project

Applications are invited for a four year Postgraduate studentship, supported by the Midlands Integrative Biosciences Training Partnership (MIBTP) and Biotechnology and Biological Sciences Research Council (BBSRC), to be undertaken within the Pharmacology and Translational Neuroscience Research Group at Aston University. The studentship is offered in collaboration with InoCardia.

The position is available to start October 2021.

Financial Support

This studentship includes a fee bursary to cover the Home fees rate, plus a maintenance allowance of at least £15,285 (subject to eligibility). This application is only available to Home-fee paying students.

Background to CASE Studentships

CASE studentships are designed to provide students with a first-rate challenging research training experience within the context of a mutually-beneficial research collaboration between academic and non-academic partner organisations. Full details on CASE studentships can be found here.

Project Outline

Calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2) are related peptides that increase heart rate and force of contraction, improve coronary blood flow and protect the heart from ischaemia. Thus they have good potential for use to treat heart disease and elevated levels are found in heart diseases, suggesting they are released as natural protectants. They all act on the same G-protein coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR). However, unusually, the pharmacology of these peptides are determined by an accessory protein, one of three receptor activity modifying proteins (RAMPs). CLR/RAMP1 gives a CGRP receptor, CLR/RAMP2 an AM receptor and CLR/RAMP3 a receptor which can be activated by AM2. We have recently shown that the situation is more complicated, as the RAMPs also dictate signalling pathways. CGRP, AM and AM2 can activate a number of signalling pathways, including cAMP, elevation of intracellular calcium and activation of MAP kinases. These are controlled by the way the receptors couple to different G proteins, particularly Gs, Gi and Gq. We have found that CLR/RAMP1 promotes coupling of CGRP to cAMP but when the same receptor is activated by AM, Gi is preferentially activated. The opposite is seen with CLR/RAMP2. AM2 shows preferential coupling to Gq and elevation of calcium. This is an extreme example of a phenomenon known as agonist bias. If we can understand why some agents selectively activate signalling pathways that give beneficial results, we can produce new drugs with fewer side effects.

In collaboration with InoCardia, we can study the actions of agents on human heart tissue / cells under physiological conditions, where heart cells alternatively contract and then are stretched as the heart refills with blood (Work-Loop model). No other system gives such a good mimic of what happens in the human body. We also have molecular modelling techniques to look at what happens to GPCRs as they couple to different G proteins. Thus we are equipped to investigate the actions of our peptides from the cellular to the molecular level.

The aims of this project are:

1) To determine the actions of CGRP, AM and AM2 on human and rat myocytes during the contractile cycle and associated pharmacology.

2) To determine the signalling pathways activated by the peptides during the contractile cycle.

3) To understand the molecular basis of the peptides and their ability to promote differential G protein coupling using molecular dynamics.

Person Specification

The successful applicant should have been awarded, or expect to achieve, a Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution) in a relevant subject. Full entry requirements for Aston University can be found on our website

Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course. Full entry and eligibility requirements for MIBTP can be found on their website

Contact information

For formal enquiries about this project contact Prof David Poyner by email at [Email Address Removed].

Submitting an application

Details of to apply for this MIBTP CASE studentship and the required documents can be found here.

If you require further information about the application process please contact the Postgraduate Admissions team at [Email Address Removed]

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