1. Research Background

As a subterranean mammal the naked mole-rat (NMR) faces a particularly challenging environment characterised by patchily available food, low O₂ and high CO₂ levels. In response naked mole-rats have evolved a suite of molecular and physiological adaptations allowing them to survive extreme hypoxia and 18 minutes under complete anoxia¹. 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 external stresses offer this animal pleiotropic protection against age-dependent decline, resistance to cancer and allow it to live an incredibly long and healthy lifespan (>30 years).

We are interested in understanding the metabolic plasticity accompanying changes in oxygen and nutrient levels in the naked mole-rat. We and others have shown multiple evidence for rewired metabolism in the naked mole-rat including immature mitochondrial morphology characterised by sparse cristae in heart and liver, neonatal-like metabolism in the heart and a switch to fructose synthesis and metabolism under hypoxia. We aim to understand the implications of such rewiring and with these insights we hope to discover novel therapeutic strategies to alleviate damage under hypoxic or ischaemic conditions pertinent to a wide range of disease states.

2. Research questions addressed by the group

We use a multidisciplinary approach to identify and understand metabolic adaptations and apply them in the context of human cardiovascular disease. We use:

• Transcriptomic and epigenomic analysis to investigate gene regulation and epigenetic remodeling under different environmental and pathological challenges (eg. Hypoxia, ischaemia)
• Metabolomics and proteomics with PTMs to map alternative routes in metabolism and the signaling pathways contributing to it

To test whether our newly identified candidates yield similar benefits in mouse models, we introduce naked mole-rat features into transgenic mouse models or cell culture systems. For example, we identified that naked mole-rats rely on fructose metabolism under hypoxia. We have generated a GLUT5 transgenic mouse which would be capable of more efficiently taking up fructose in heart and other tissues and are testing it in models of hypoxia and ischaemia/reperfusion.

We have shown that naked mole-rats have many retained neonatal-like features in the heart, including a neonatal metabolism reliant on glycolysis rather than fatty acid oxidation with distinctly immature mitochondrial morphology. These features amongst others have been implicated in allowing regeneration in neonatal myocardium in the first days of life after which regenerative capacity is shut off. Given these retained neonatal-like features in the naked mole-rat, we are investigating the ability of an adult naked mole-rat heart to regenerate myocardium post injury using a myocardial infarction model.

3. Possible Project(s)

Previous work in the lab has identified several interesting metabolites and alternate metabolic pathways which are differentially regulated in the naked mole-rat compared to the mouse under baseline or extreme hypoxic conditions. Several projects exist in the lab to further characterise and understand how and why the naked mole-rat uses these metabolites and metabolic pathways. Do they rewire metabolism and can they promote a beneficial state to either ward off diseases or protect cells under hypoxia? Furthermore, we want to investigate these same pathways in mouse and human by using cell lines or transgenic mouse models.

Examples of projects:

• 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 and whether it is involved in the naked mole-rat’s metabolic plasticity.
• We have identified several metabolites that accumulate in the naked mole-rat under hypoxia. We want to test whether these metabolites act as signaling molecules to switch on alternative metabolic programs that are protective under stressful conditions like hypoxia.

4. Applied Methods and model organisms

• Using a non-standard animal model the naked mole-rat as well as transgenic mouse models
• Langerdorrf ex vivo heart model
• Cell biology
• Molecular and biochemistry techniques
• RNAseq, ATACseq, ChIPseq
• Mass-spectrometry
• Animal phenotyping and in vivo physiology

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, or in vivo mouse models are encouraged to apply.

6. References and key publications:

• Buffenstein R, Amoroso V, Andziak B, Avdieiev S, Azpurua J, Barker AJ, Bennett NC, Brieño-Enríquez MA, Bronner GN, Coen C, Delaney MA, Dengler-CrishCM, Edrey YH, Faulkes CG, Frankel D, Friedlander G, Gibney PA, Gorbunova V, HineC, Holmes MM, Jarvis JUM, Kawamura Y, Kutsukake N, Kenyon C, Khaled WT, Kikusui, T, Kissil J, Lagestee S, Larson J, Lauer A, Lavrenchenko LA, Lee A, Levitt JB, Lewin GR, Lewis Hardell KN, Lin TD, Mason MJ, McCloskey D, McMahon M, Miura K, Mogi K, Narayan V, O'Connor TP, Okanoya K, O'Riain MJ, Park TJ, Place NJ, Podshivalova K, Pamenter ME, Pyott SJ, Reznick J, Ruby JG, Salmon AB, Santos-Sacchi J, Sarko DK, Seluanov A, Shepard A, Smith M, Storey KB, Tian X, Vice EN, Viltard M, Watarai A, Wywial E, Yamakawa M, Zemlemerova ED, Zions M, Smith ESJ.The naked truth: a comprehensive clarification and classification of current 'myths' in naked mole-rat biology. Biol Rev Camb Philos Soc. 2022 Feb;97(1):115-140
• Reznick J, Park TJ, Lewin GR. A Sweet Story of Metabolic Innovation in the Naked Mole-Rat. Adv Exp Med Biol. 2021;1319:271-286. doi:10.1007/978-3-030-65943-1_10. PMID: 34424520
• Park TJ*, Reznick J*, Peterson BL, Blass G, Omerbašić D, Bennett NC, Kuich PHJL, Zasada C, Browe BM, Hamann W, Applegate DT, Radke MH, Kosten T, Lutermann H, Gavaghan V, Eigenbrod O, Bégay V, Amoroso VG, Govind V, Minshall RD, Smith ESJ, Larson J, Gotthardt M, Kempa S, Lewin GR. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science. 2017 Apr 21;356(6335):307-311.

*equal contribution