Principal Supervisor: Dr Nina Storey - Department of Molecular and Cell Biology
Co-supervisor: Dr Gary Willars
PhD project title: Peptide hormone glucagon-like peptide-1 (GLP-1) signalling in cardiac muscle
University of Registration: University of Leicester
Type 2 diabetes is a common metabolic disorder and the prevalence is increasing worldwide. Despite a range of therapeutic interventions, many patients remain poorly controlled and there is increased morbidity and mortality, particularly through cardiovascular disease. As a consequence there is a drive to develop improved therapies that target both the underlying metabolic problems and the associated complications. To maximally exploit novel therapeutic possibilities there is a need not only to consider blood glucose control but to fully understand interactions of new drugs with other systems and in particular the cardiovascular system. It is critical that new drugs are specific to the target signalling pathways and organs with limited deleterious interactions within the body. In recent years, the ability of the gut peptide hormone, glucagon-like peptide-1 (GLP-1), to promote glucose-dependent insulin release has made this system an attractive therapeutic target in type 2 diabetes. Indeed, with the current drive to generate small-molecule drugs, orally-active GLP-1 receptor agonists have been developed and used clinically. Additionally, small molecule inhibitors of the enzyme that degrades GLP-1, dipeptidyl peptidase-4 (DPP-IV), have been created. The DPP-IV inhibitors increases the life span of GLP-1 in the blood stream to prolong its insulin secreting activity and lower blood glucose. These newly developed GLP-1 related drugs are an attractive alternative to current diabetic therapies. Notably, GLP-1 receptor ligands and DPP-IV inhibitors have effects on the cardiovascular system which have the potential to be favourable, for example lowering blood pressure and protecting the heart from ischaemic injury. Although these mechanisms are not fully understood, they have the potential to contribute significantly to the beneficial effects of such anti-diabetic drugs. The purpose of this project is to understand how GLP-1 signals in cardiac muscle and what physiological effects occur and to determine if there effects are indeed beneficial.
The major post-prandial circulating active form of GLP-1 is the GLP-1(7-36) amide peptide, which is rapidly cleaved by DPP-IV to a shorter peptide GLP-1 (9-36) amide that circulates at higher levels. The function of the shorter GLP-1 (9-36) amide is unclear. We have shown that both the longer and shorter forms of GLP-1 peptide have protective effects in isolated cardiac muscle cells; increasing the recovery of contractile function after experimental manipulations that mimic the metabolic changes seen during myocardial infarction. We have also observed GLP-1 mediated modulation of the KATP channel which is a key effector in cardioprotection. The proposed project will examine the signaling pathways of a variety of GLP-1 related receptor ligands to explore the mechanisms leading to their protective effects, particularly focusing on electrophysiological determination of KATP channel modulation, cellular Ca2+ handling by fluorescence imaging and determination of the activity of a variety of other key signal transduction pathways. Identification of the mechanisms involved in cardioprotection will facilitate the use or design of receptor ligands that bias their signaling toward these beneficial pathways to ensure full exploitation of the GLP-1 receptor as a therapeutic target in type 2 diabetes.
Our overall hypothesis is that KATP channels play a central role in stress protection of cardiac muscle, including signaling pathways from the G-protein coupled GLP-1 receptor. Additional hypotheses are: 1) Both GLP-1(7-36) amide, and the shorter peptide GLP-1 (9-36) amide are cardioprotective due to modulation of KATP channels. 2) The signaling pathways involves cAMP signaling with PKA and EPAC activation of KATP channels; 3) The GLP-1 signaling pathway is important for protection of human myocardium.
This project contributes to the recent focus on the effectiveness of anti-diabetic therapeutic strategies and the drive to find new and better drugs.
BBSRC Strategic Research Priority: Molecules, cells and systems
Techniques that will be undertaken during the project:
- Single cell patch-clamping whole-cell voltage and current clamp and single-channel recordings
- Cardiac muscle contraction assays
- Cell viability assays
- Fluorescent cell imaging for cell calcium
- Cell physiology techniques such as western blotting
- Radio ligand specific binding assays
Contact: Dr Nina Storey, University of Leicester