- Sydney Heart Bank (dos Remedios, Lal, Li)
Development of the Sydney Heart Bank Database
Construction of Human Myocardial Tissue Microarrays
- Molecular and cellular contractility in human heart disease (Li, dos Remedios)
The pathophysiology of Myosin Binding Protein C mutations in Hypertrophic cardiomyopathy
The role of myosin super-relaxed state in the human heart
- Human Cardiac regeneration (Lal, dos Remedios)
Cardiac regeneration in the adult human heart
Project 1: Development of the Sydney Heart Bank Database
The Sydney Heart Bank is now transitioning from a liquid to vapour phase storage system. Clinical information from each patient needs to be linked to the 20,000 plus samples in the bank. This project involves developing a database with all the information (e.g. clinical, physical location of the sample, who has used tissue from a specific patient, what they were researching and the data they generated) required for a range of heart failure research.
Project 2: Construction of Human Myocardial Tissue Microarrays
We provide laboratories with sections of human cardiac tissue microarrays (TMA) as a part of the Sydney Heart Bank’s core facility. A single TMA can contain up to 200 cores of tissue that enables researchers to perform immunofluorescence or immunohistochemistry studies on a range of different heart failures, or to compare the failing to non-failing donor heart. TMAs are a high throughput method of screening for whether the protein of interest is expressed in the human heart, and where it is localised. The project itself involves constructing custom TMAs to suit a range of internal and external heart failure research projects.
Project 3: The pathophysiology of Myosin Binding Protein C mutations in Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an inherited heart disease that causes the heart wall to severely thicken. Over half of these patients carry gene mutation(s) of the sarcomere, i.e. proteins that make up the basic contractile unit. One of the most frequently mutated genes is myosin binding protein C (MyBP-C) with over 300 mutations identified so far. We have examined the molecular and cellular function of this protein in the heart. On the molecular level, we utilise native filament motility assays to determine how MyBP-C regulates sliding velocity of thin filaments. This is then correlated with the examination of micro-dissected fibres from patients with HCM who had undergone the cardiomyectomy procedure. We aim to investigate the function of MyBP-C intrinsic to the human heart in order to identify potential therapeutics.
Project 4: The role of myosin super-relaxed state in the human heart
The super-relaxed (SRX) state of the myosin motor protein represents a portion of non-force generating myosin bound to the myosin core. In contrast, regular relaxed myosin is not restricted to the myosin rod and as such can reach across to actin to promote muscle contraction. SRX myosin exhibits a far slower ATP turnover than regular relaxed myosin, and thus reduces the energy utilisation of the heart. SRX was previously demonstrated to modulate cardiac metabolism, and may be cardioprotective during stressful ischaemic events.
Heart failure is the number one cause of death in humans. However, despite the years of research surrounding this topic, the mechanism is so far poorly understood. Therefore the understanding gained from this study of how heart failure affects the energetics of the heart may provide a new target for non-invasive pharmacological treatment of heart failure.
Project 5: Cardiac regeneration in the adult human heart
It is increasingly evident that non-human mammalian hearts have excellent regenerative capacity during development, slows down after birth, but may be re-activated in post-natal life. Recent studies on cardiomyocyte growth and proliferation reveal that human hearts also possess proliferative capacity after birth. Initial models suggested that approximately 1% of cardiomyocytes are turned over each year when we are young and that this rate declines to about half of that by age 75. This would imply that 50% of our cardiomyocytes are replaced in our lifespan.
All of this raises the possibility that the loss of myocytes in a failing heart may be countered by stimulating regeneration of new, functional myocardium from the remaining cardiac cells. The advantage here is that the progeny will inherit the correct electromechanical connections, meaning that the new cells are less prone to induce potentially fatal arrhythmias. In addition, it is likely that the extent and duration of cell proliferation can be better controlled.
With our research collaborators at the University of Pittsburgh and Harvard University, we are examining the intrinsic proliferative capacity of human hearts in health and disease as we look towards the stimulation of cardiomyocyte proliferation as being a promising therapeutic approach for treating heart failure.