INVESTIGATING THE ROLE OF RUNX1 IN THE HEART POST-MYOCARDIAL INFARCTION

Coronary heart disease (CHD) is the UK's single biggest killer, leading to the death of nearly one in six men and one in ten women in the country. Approximately 2.3 million people in the UK are living with CHD. In 2009, the healthcare costs of this (medications, accident & emergency, primary/outpatient/inpatient care) amounted to nearly £2 billion, whilst informal care costs and productivity losses due to mortality and morbidity amounted to an additional £5 billion. The incidence of CHD correlates strongly with deprivation - mortality rates are almost twice as high in deprived areas compared with affluent areas.

CHD occurs when the blood vessels of the heart (coronary arteries) become narrowed by fatty material (atheroma), reducing blood flow to the heart muscle. If the atheroma breaks off it can lead to the formation of a blood clot that could potentially block the coronary artery, cutting off the oxygen-rich blood supply to a part of the heart muscle and risking irreversible damage. The death of this part of the heart muscle is called a heart attack, also known as myocardial infarction (MI).

Whilst the heart muscle that dies forms a scar, the surviving heart muscle around the scar undergoes numerous maladaptive changes that can dictate the outcome for the patient. Collectively, these changes are called pathological cardiac remodelling and can lead to a dilated heart that is unable to pump efficiently. A significant proportion of post-MI patients undergo progressive worsening of pathological cardiac remodelling and develop heart failure (HF), meaning that the heart can no longer pump enough blood to meet the needs of the body. Although improving, population morbidity and mortality remain high and new treatments are urgently required for patients with MI and HF.

Runx1 is a protein that regulates the activity and expression of a number of other proteins important for the normal functioning of the body. Recently it has been discovered in patients with MI that increased levels of Runx1 are produced in the surviving heart muscle around the scar. Until now the function of Runx1 in the heart remained unknown. We have induced MI in a genetically modified mouse with selective reduction of Runx1 in the heart muscle cells (cardiomyocytes). Our experiments demonstrate compelling evidence that Runx1 is linked to how well the heart is able to pump post-MI. This proposal aims to uncover the mechanisms involved in this important link and in doing so drive forward future studies to determine the therapeutic potential of this novel target.

Mortality of patients with MI and HF remains high despite optimal current medical therapy. New options that limit adverse cardiac remodelling and preserve LV function post-MI are urgently required. Runx1 is a transcription factor essential for the normal functioning of numerous organs and tissues, the most well-known of which is its critical role in haematopoiesis and Acute Myeloid Leukaemia. Recently discovered in the heart, Runx1 is increased in cardiomyocytes in the border zone myocardium of both patients with MI and in animal models of MI. Until now the function of Runx1 in the heart remained unknown. We have utilised CreLoxP technology to generate tamoxifen-inducible cardiomyocyte-specific conditional Runx1 knockout mice. One week following a single intra-peritoneal injection of tamoxifen, we induced MI (with an infarct size of 30-35% of LV) in adult Runx1 knockout mice and phenotyped them using echocardiography and pressure-volume catheters. Remarkably, whilst control mice demonstrated the expected decrease in LV contractility, wall thinning, eccentric hypertrophy and impaired cardiomyocyte calcium handling, Runx1 knockout mice with MI were protected from these adverse effects. We have therefore identified a novel target with therapeutic potential in the setting of MI. This proposal will provide mechanistic insight into the improved cardiac phenotype observed in Runx1 knockout mice and thereby enhance our understanding of cardiac remodelling post-MI, providing a platform for future translational studies to develop new therapeutic options for post-MI patients.

The findings of this research will inform the development of new strategies to treat and manage patients with MI, potentially benefiting the following communities of 'users':

1. Pharmaceutical and healthcare industry representatives whose primary business is the development of new treatments
2. Clinicians managing patients with heart failure and with an interest in translational medicine
3. Patients with MI, their families and supporting organisations/agencies

The data obtained will also be of immediate impact to those in the academic cardiac research community working in the field of cardiac remodelling, particularly cardiomyocyte hypertrophy and calcium handling, and will be relevant to mathematical modellers and biophysicists interested in the factors that influence cardiac geometry post-MI.

In the longer term it is likely that the data obtained from this study will directly inform the development of a therapeutic option centring on altering Runx1 expression/activity. At this stage we will utilise the resources of the University of Glasgow's Research Strategy & Innovation Office to engage with people from the pharmaceutical and healthcare industries concerned with the development of new treatments; we have already initiated such discussions using our pilot data.

Coronary heart disease costs the UK approximately £7 billion per year and affects some 2.3 million people. The identification of novel targets and the development of new therapeutic approaches to treat patients with MI is of paramount importance, and could deliver significant benefits to the health and quality of life of patients and to the UK and global economy. Proposals with translational potential such as this one will ensure that researchers in the UK continue to lead the way in the global market in developing new treatments for major chronic diseases. Whilst acknowledging that the latter is a long-term goal (>10 years) we are convinced by the data and plan of work presented in this proposal that such an impact is achievable. The research plan also affords the additional benefit of a suite of transferable skills that will be acquired by the post-doctoral research associate, including project management, data handling, communication and public engagement. These skills will be nurtured in line with the mission of the Glasgow Cardiovascular Research Centre to foster the career development of young researchers.