4-year PhD Studentship: Regional variation in transcriptional patterns of myocardial metabolism within the same heart early after myocardial infarction: mechanistic validation and therapeutic pathways

The occlusion of a coronary artery leads to myocardial infarction(MI), an ischemic time-dependent irreversible injury including apoptosis, necrosis, impaired cell homeostasis and reduced/impaired energy production(1,2). Currently, the treatment of MI is early re-opening of the occluded vessel to reduce MI size and prevent heart failure (HF). No drugs are available.

The heart is a ‘metabolic omnivore’ able to use various substrates in the TCA cycle to maximise the availability of substrate and metabolic intermediates, spatial/temporal distribution of metabolic enzymes and respond to changes in cardiac workload(3). Though the healthy heart can shift to lactate metabolism anaerobically during exercise, the phenomenon of producing ATP via lactate despite adequate oxygen, termed aerobic glycolysis, or the Warburg effect, has not been described in the MI scenario(3). Improved understanding of the early regional metabolic alterations induced by MI may provide new biomarkers to identify patients at increased risk of sustaining significant adverse remodelling. The aim of this PhD project is to build on our strong preliminary data to investigate and validate regional differences in metabolic profiles and transcriptional patterns across peri-infarct and remote viable regions of the same infarcted heart to identify molecular signatures associated with left ventricular impairment and adverse remodelling.

Aims and objectives

Our preliminary study in a porcine MI model indicates increased glycolysis, reduced oxidative phosphorylation and signs of aerobic glycolytic metabolism(Warburg effect) in the remote viable myocardium and reduced glycolysis and TCA activity with signs of foetal metabolic pattern and insulin-resistance in the infarcted region. This project aims to 1) characterize, using proteomic and transcriptomic technology, the changes in protein complexes central to the regional metabolic remodeling of the infarcted heart and 2) identify key molecular signatures in-vitro on fresh and fixed specimens and from available serial clinical imaging associated with Warburg effect, HF and adverse left ventricular remodelling.

Methodology

We will use samples from 18 large pigs (10 subjected to MI and 8 healthy controls) as well as clinical imaging with focus on left ventricular (LV) function, scar and LV remodelling obtained with cardiac magnetic resonance (CMR). In addition, we will use fresh samples from porcine and rat heart with focus on LV samples from peri-infarct and remote viable regions to ascertain gene expression, protein and enzymatic activity of, among others, Glucose transport 1(GLUT1), Glucose transport 4 (GLUT4), Ankyrin-2 (ANK2), Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), Lactate dehydrogenase-A (LDHA), mitochondrial Complex I subunit 1 (ND1), mitochondrial Transcription Factor-A (TFAM), Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-alpha), Protein kinase B (AKT1), AKT substrate of 160 kDa (AS160) and Hypoxia-inducible factor 1-alpha (HIF1-alpha). Validation of key signatures will be via western blotting.

Proteomic and transcriptomic mapping: To identify proteins/pathways central to regional metabolic changes, protein and transcript expression in isolated cardiac myocytes (rat/pig) derived from across different LV regions of the infarcted heart in culture will be mapped using Proteomic and RNA-seq transcriptomic analysis.

Adult cardiac myocyte isolation and culture: Cardiac myocytes from rat and pig will be isolated and cultured using established protocols(4,5).

How to apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol.

Please visit the Faculty of Health Sciences website for details of how to apply