1. Research Background
Metabolic pathways are dynamic networks that support tissue homeostasis and prompt changes in cell phenotype. We aim to understand metabolic adaptations and their role in different cellular and environmental contexts with a focus on hypoxia, regeneration and diseased states such as myocardial ischaemia and diabetes. We use a non-standard animal model, the naked mole-rat, which is a long-lived eusocial mammal (lifespan >35 years) with several unique features including extreme hypoxia resistance to understand metabolic plasticity in the face of environmental challenges. 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.
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. We ask whether neonatal-like features retained in adult naked mole-rat hearts facilitate faster repair and promote regeneration and by generating transgenic mouse models harbouring naked mole-rat-like traits we will verify whether these are also beneficial in mice under different environmental and pathological contexts.
2. Research questions addressed by the group:
- We have identified several examples of metabolic rewiring in the naked mole-rat including a switch to fructose metabolism, alteration in mitochondrial function and retention of neonatal-like traits into adult life. Now, we want to understand not only the biological significance of these alternate pathways but also how this rewiring is achieved. We are combining metabolomic analysis with investigation into the epigenetic and post-translational regulation of the naked mole-rat and mouse metabolism across different environmental challenges.
- 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 metabolize fructose which protects them from hypoxia. Several lines of evidence points to this pathway being conserved in other organisms and cell types under hypoxic pressure. By overexpressing fructose metabolizing genes in the mouse, we want to see whether enhancing fructose metabolism can offer protection in mouse models of hypoxia, myocardial infarction and ischaemia/reperfusion.
- Inhibiting insulin/IGF-1 signaling extends lifespan and delays age-related disease in species throughout the animal kingdom. Naked mole-rats have an altered insulin/IGF1 signaling pathway and we want to interrogate how this contributes to the animal’s longevity, reproduction and social organization.
3. Possible project(s):
Possible projects include:
- Epigenetic regulation of metabolism in the naked mole-rat under different environmental challenges and pathological interventions.
- Characterization of transgenic mice with naked mole-rat like features in the context of hypoxia tolerance, ischaemia/reperfusion injury and diabetes. Specifically, does enhanced fructose metabolism improve survival in hypoxia and heart function after myocardial infarction.
- Characterization of the insulin/IGF signalling pathway in the naked mole-rat and its contribution to the animal’s long lifespan and social organisation.
- We have identified a small molecule which lowers insulin levels. Given that inhibition of insulin leads to extended lifespan we want to test this novel small molecule in the context of extending lifespan/healthspan in aged mice.
4. Applied Methods and model organisms:
- Using a non-standard animal model the naked mole-rat as well as transgenic mouse models
- RNAseq, ATACseq, ChIPseq
- Cell biology
- Molecular and biochemistry techniques
- Animal phenotyping and in vivo physiology
- In vivo surgeries to model cardiac infarction
5. Desirable skills and qualifications:
We seek a highly motivated and creative candidate to join an enthusiastic and collaborative team in a vibrant scientific environment. Candidates with a background in molecular biology, biochemistry, computational biology or in vivo mouse models are encouraged to apply.