DJ-1 as a novel target for cardioprotection

Heart attacks are a leading cause of death and disability in the UK. Therefore, new treatment strategies are required to reduce the damage to the heart muscle during a heart attack in order to prevent the onset of heart failure and improve health outcomes. Whether heart muscle is able to recover following a heart attack is crucially dependent on the function of its mitochondria, the powerhouse of the cells, generating the energy required for normal heart function. This research proposal investigates the role of DJ-1, a protein within the mitochondria which may provide a novel target for protecting the heart muscle during a heart attack.

The overall research objective will be to investigate DJ-1 as a novel mitochondrial target for protecting the heart against the detrimental effects of ischaemia-reperfusion injury (IRI).

1) Investigation of DJ-1 Function (In Vitro):
The first objective will be to characterise the cardioprotective effect of DJ-1 using the HL-1 cardiac cell-line. We will investigate the effects of ablating DJ-1 using siRNA on mitochondrial function and susceptibility to IRI. Using different DJ-1 mutants, we will also determine how its subcellular localisation influences its cardioprotective effect.

2) Investigation of DJ-1 Function (In Vivo):
The second objective will be to investigate the effect of endogenous DJ-1 in the adult heart. We will investigate the effect of DJ-1 ablation & DJ-1 over-expression in the adult murine heart on in situ myocardial infarct size & post-MI remodelling and the development of heart failure using cardiac MRI to assess these endpoints.

3) Investigation of Mechanism of Cardioprotection bt DJ-1:
The third objective will be to investigate the mechanisms underlying the cardioprotection elicited by DJ-1. We will investigate the effect of DJ-1 on mitochondrial function by measuring the production of oxidative stress during IRI (confocal microscopy), mitochondrial respiration (SeaHorse Biosciences Analyzer), & mitochondrial morphology (confocal microscopy). In addition, we will investigate the effect of DJ-1 on an anti-apoptotic mechanism in which Akt downregulates the pro-apoptotic DAXX-ASK-1 pathway.

4) Investigation of effects of pharmacological modulation of DJ-1:
The fourth & final objective will be to investigate pharmacological modulation of DJ-1 as a novel therapeutic cardioprotective strategy using a recently described small molecule activator of DJ-1 called phenylbutyrate. We will investigate whether this drug can protect the heart from IRI using adult murine cardiomyocytes and an in vivo murine model of acute & chronic MI.

Understanding how to induce protective mechanisms within the heart has potentially far-reaching benefit to many heart attack victims worldwide. There are key gaps in our understanding of what makes one person's heart more able to withstand a heart attack than others and the role that mitochondria play. This research, which aims to examine a new way of treating heart disease by targeting a novel mitochondrial protein DJ-1, will undoubtedly contribute to a better understanding of the pathophysiology of heart disease which is the leading cause of death in the UK.

In addition to academic beneficiaries (please refer to Academic Beneficiaries), the findings are fundamental to future development of potential pharmaceutical compounds that can specifically target DJ-1 to treat heart disease and potentially other diseases that involve dysregulation of mitochondrial function. Providing a new and effective treatment for chronic heart disease can eventually improve patient's wellbeing and alleviate the huge economic burden to healthcare system. Post target validation, potential new treatments targetting DJ-1 will take between 7-15 years to get to market.