Periodic Reporting for period 2 - METAMOLE (Naked mole-rats to mice: metabolic reprogramming to prevent ischaemic injury)
Reporting period: 2022-07-01 to 2023-12-31
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.
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.
1. We have performed epigenetic, genomic, proteomic and metabolomic analysis to understand metabolic plasticity and cellular reprogramming under hypoxic or ischaemic conditions in the naked mole-rat that distinguishes its response from that of the mouse. We have discovered several potential key genes, metabolites and pathways which allow the naked mole-rat an optimized way to cope with such damaging stressors.
2. We have overexpressed the fructose transporter GLUT5 in the mouse and have validated the overexpression of the transporter across different tissues including the heart. we are now analysing ischaemia/reperfusion studies performed on GLUT5 transgenic hearts ex vivo to understand whether, in the same capacity as in the naked mole-rat, increased fructose metabolism protects mouse hearts from injury associated with ischaemia/reperfusion.
3. We are in the process of analysing the intrinsic ability of the naked mole-rat heart to regenerate post-injury.
2. We have overexpressed the fructose transporter GLUT5 in the mouse and have validated the overexpression of the transporter across different tissues including the heart. we are now analysing ischaemia/reperfusion studies performed on GLUT5 transgenic hearts ex vivo to understand whether, in the same capacity as in the naked mole-rat, increased fructose metabolism protects mouse hearts from injury associated with ischaemia/reperfusion.
3. We are in the process of analysing the intrinsic ability of the naked mole-rat heart to regenerate post-injury.
We have discovered several non-canonical metabolites and pathways that the naked mole-rat utilizes under ischemia and we hope to introduce these now into the mouse with the outlook to develop these strategies into therapeutics.