Investigating formyl peptide receptor (FPR) signalling to better treat myocardial infarction
Myocardial infarction (MI) and resultant heart failure remain the leading cause of death and disability in Australia. Current treatments for MI restore blood flow to the ischaemic area, however they may elicit further myocardial damage (termed reperfusion injury) via aberrant inflammation which can account for up to 50% of the final infarct size. There are currently no drugs available to treat reperfusion injury which highlights the crucial need for new and innovative cardioprotective therapies aimed at treating MI and preventing the onset of heart failure. The formyl peptide receptors (FPR), a family of G protein-coupled receptors (GPCRs), are involved in the regulation and resolution of inflammation and thus represent a novel therapeutic target for MI.
An important distinguishing feature of FPRs is their ability to interact with structurally diverse ligands (lipids, proteins, peptides and small molecules) to stimulate both pro- and anti-inflammatory responses downstream of receptor activation. How a single receptor can illicit opposing outcomes even within the same cell type is not firmly understood but one emerging explanation is biased signalling. Biased signalling refers to the ability of ligands to stabilise unique active receptor conformations to selectively activate a subset of intracellular signalling pathways. This phenomenon provides the therapeutic opportunity to promote beneficial signal transduction in the absence of on-target adverse effects. Our laboratory has recently published on a biased FPR small molecule compound that promotes myocardial cell survival and myocardial protection in a model of ischaemia-reperfusion injury. We want to further probe the pharmacology of the FPRs to determine what drives a cardioprotective, anti-inflammatory signalling profile.
The aim of this Honours project is to investigate the diverse signalling profile of FPR ligands at the FPR1 and FPR2 receptor subtypes and quantify their biased signalling fingerprint to inform rational drug design.
This project will utilise in vitro cell signalling techniques to examine the binding and efficacy of small molecules and endogenous peptides at the FPR1 and FPR2 in primary and engineered FPR cell lines. The student will gain proficiencies in aseptic cell culture technique and FRET and BRET-based technologies to measure intracellular signalling molecules (cAMP, pERK1/2, Ca2+ etc) using high-end equipment such as the PHERAstar, Envision and FDSS/μCELL imaging microplate readers.