Early molecular causes of heart enlargement and failure

Project summary

The abnormal enlargement of the heart, also known as cardiac hypertrophy, is one of the most potent risk factors for heart failure and premature death. Small RNA molecules called microRNAs (miRNAs) have been revealed as key controllers of gene expression and highly relevant to the molecular mechanisms for cardiac diseases. The miRNAs are also amenable to a new developing range of treatment strategies. We have developed a unique model of human polygenic cardiac hypertrophy – the Hypertrophic Heart Rat (HHR) – in which the heart has a reduced complement of smaller cardiomyocytes soon after birth, which leads to heart enlargement and failure latter in life. In this project we will use a second generation hybrids of the HHR and NHR to simultaneously acquire transcriptome-wide patterns of expression of miRNA and genes, and genome-wide genotypes that we shall link with key phenotypes (the numbers, size and morphology of cardiomyocytes) in neonatal hearts. These studies will provide an understanding of the two-way interaction between genes and miRNA that underpin cardiac hypertrophy and allow us to test targeted, brief miRNA-inhibition therapeutic interventions to prevent/treat hypertrophy and its complications.

Research team: Prof Fadi Charchar, Dr Francine Marques, Mr Sean Quarrell (Federation University Australia), Dr Claire Curl, Mrs Claire Chevalier (University of Melbourne), Dr Paul Levandowski (Deakin University).

The Y chromosome and cardiovascular disease

Project summary

We have previously shown that genetic variation within the male-specific region of the Y chromosome is associated with the risk of coronary artery disease (CAD), independent of traditional cardiovascular risk factors and possibly through a modulating effect of the Y on adaptive immunity and response to inflammation in a recent publication in the Lancet. The exact molecular mechanisms that cause this increase in risk are yet unknown. Novel data from our group have shown that the Y chromosome harbours non-coding RNA that may be involved in this association. Furthermore we find increased expression in two Y chromosome genes in subjects at higher risk of CAD. In the current project we aim to identify whether (i) microRNA and/or (ii) lncRNA on the Y mediate this association between the ancient paternal lineages of the human Y chromosome and CAD.

Research team: Prof Fadi Charchar, Dr Guat Chew, Mrs Elsa Molina (Federation University Australia), Dr Stephen Myers (University of Tasmania), Prof Stephen Harrap (University of Melbourne), Prof Nilesh Samani, Dr Maciej Tomaszewski, Dr James Eales (University of Leicester).

Copy number variation and cardiovascular disease

Project summary

High blood pressure, or hypertension, is estimated to cause 7.1 million deaths worldwide annually. The relative inadequacy of currents treatments in terms of efficacy and side effects means that new approaches are needed. Since approximately 40% of blood pressure (BP) variation is genetically determined, molecular/genetic targets offer potential in this regard. There has been an intensive international search for genes associated with hypertension using single nucleotide polymorphisms (SNPs), but these studies have overlooked structural variations such as Copy Number Variations (CNV), which are likely to contribute to the condition. The aims of the project are to determine whether CNVs in the above physiologically strong candidate genes contribute to the pathogenesis of human hypertension 1) in collaboration with our AIS we will develop assays of copy numbers to our knowledge never used in Australia. 2) We will apply these assays to a large cohort from Australia specifically designed to study the genetics of cardiovascular risk to determine association between copy number and hypertension or other cardiovascular traits and we will follow up identified associations with large cohorts from the United Kingdom, and cohorts from other European populations. 3) To determine whether these changes in copy numbers in human subjects lead to potential physiologic mechanisms, we will determine if there is an increase or decrease in expression of these hypertension genes in the kidneys from normal and hypertensive subjects and develop an RNA knockout assays in vitro.

Research team: Prof Fadi Charchar, Dr Francine Marques (Federation University Australia), Prof Stephen Harrap (University of Melbourne).

The effect of exercise on molecular machinery

Project summary

White blood cell telomere dynamics are vital for chromosomal integrity and shortening is associated with ageing and numerous chronic diseases, most of which are either prevented or managed by physical exercise. To date, the current literature is unclear as to the ideal dose of physical activity/exercise training that confers aids telomere maintenance. Moderate amounts of physical activity have been shown to be ideal, but others have shown no such benefit. We have, however, demonstrated that ultra-marathon runners have 11% longer white blood cell telomeres compared to healthy controls (Denham et al., 2013), thus supporting previous findings suggesting that endurance athletes have longer telomeres than apparently healthy or sedentary controls. This project identify whether extensive exercise training is associated with longer telomeres and uncover certain genes responsible for the attenuated telomere attrition conferred by endurance exercise.

Research team: Prof Fadi Charchar, Dr Brendan O'Brien, Mr Warrick Chilton, Mr Joshua Denham (Federation University Australia), Dr Maciej Tomaszewski (University of Leicester).