As a subterranean mammal the naked mole-rat faces a particularly challenging environment characterised by patchily available food, low O2 and high CO2 levels. In response to these pressures naked mole-rats have evolved a suite of molecular and physiological adaptations. These environmental challenges closely parallel the cellular milieu encountered in diseased states. As such, we believe that the adaptations evolved in the naked mole-rat as a response to its environmental stresses offer this animal pleiotropic protection against age-dependent decline.
Our primary focus is on metabolism. What are the means by which the naked mole-rat remodels its metabolism to counteract environmental challenges such as hypoxia? Since many human diseases are defined by metabolic abnormalities, we want to understand the nuances of metabolic plasticity leading to either dysfunctional disease- or adaptive health-promoting states.
Research Area 1
We have identified several examples of metabolic rewiring in response to hypoxia in the naked mole-rat including a switch to fructose metabolism and retention of neonatal-like traits into adult life. Now we want to understand how this rewiring is achieved by interrogating the epigenetic and post-translational regulation across different environmental challenges.
What are the master regulators guiding distinct transcriptional programmes under specific environmental and cellular contexts and can we access these to promote beneficial cellular states?
Research Area 2
What happens when you introduce naked mole-rat features into mice? We are generating different transgenic mouse models with naked mole-rat like traits. For example, naked mole-rats have evolved an efficient way to metabolise fructose which protects them from hypoxia. By ectopically overexpressing fructose metabolising genes in the mouse, we want to see whether this pathway can offer similar protection under hypoxia, myocardial infarction and ischaemia/reperfusion models.
Research Area 3
The naked mole-rat is resilient to extreme environmental stress. Does this resilience simultaneously offer naked mole-rats protection under pathological condition such as myocardial infarction or cardiac hypertrophy. Our goal is to understand how a mammal exquisitely evolved to deal with extreme environments uses these adaptations in the face of clinical conditions. The naked mole-rat may offer us novel and innovative therapeutic strategies against ageing-related disease.
Research Area 4
Naked mole-rat metabolism is rewired to use alternative pathways as a response to living under harsh conditions. Similarities in its metabolism can be seen in distinct cellular systems, such as cancer cells and stem cells. Our goal is to understand the metabolic routes the naked mole-rat uses under different environmental and pathological contexts. Understanding these metabolic decisions may shed light not only on extended lifespan but also onto cancer and stem cell biology.
ERC Starting Grant