Cardiovascular disease remains the leading cause of death worldwide due in part to the limited capacity of the adult mammalian heart to regenerate. Although the heart retains the ability to regenerate in some lower vertebrates (e.g. zebrafish and newts) and during the early neonatal period in mammals , adult mammals do not retain the capacity to replenish the heart with sufficient cardiomyocytes to restore function following injury, despite a limited ability of adult mammalian cardiomyocytes to re-enter the cell-cycle. The current standard of care for patients with heart failure is suboptimal, with medications primarily aimed at managing symptoms and neurohormonal activation, but not targeting the underlying myocardial pathophysiology. The naked mole-rat, is the longest-lived mammal and has evolved a panel of adaptations towards its extreme and hostile environment. Our hypothesis asks whether mammals with extreme longevity also possess unexplored regenerative potential that could yield novel molecular insights that can be harnessed for medical application, such as treatment of heart failure. We have shown that naked mole-rats possess certain neonatal-like qualities in the adult myocardium, possibly giving them the potential to regenerate. Since heart failure is not only a burden on the individual but also on society, novel insights from these non-model organisms may bring about therapeutic strategy to improve the quality of life in the current ageing population but also improve productivity and reduce burden on society as a whole.
The overall Objectives is to:
1. Understand the molecular underpinnings behind the naked mole-rats rewired metabolism and its maintained neonatal state in the heart. Insights from these studies provide important clues to understand what makes a regenerative heart and the metabolic milieu and regulation required to deal successfully with stressful cellular environments found in heart disease (eg. hypoxia, ischaemia/reperfusion)
2. Introduce naked mole-rat traits into the mouse via transgenesis. The traits introduced will be those that we believe differentiate this species from the mouse and offer it optimized fitness to deal with ischemia or potentially give rise to regenerative capacity. This objective will test whether a single candidate alone, first discovered in the naked mole-rat, can be targeted or introduced to achieve therapeutic outcome in conditions of heart injury or heart failure.
3. Investigate the regenerative capacity of the naked mole-rat heart and thus establish the naked mole-rat as the first adult mammalian model of heart regeneration.
