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Naked Mole-Rat Initiative

The University of Cambridge Naked Mole-Rat Initiative 

The naked mole-rat (Heterocephalus glaber) is a mammal with a truly bizarre appearance, looking like an elongated cocktail sausage with large, protruding teeth. Naked mole-rats live in large underground colonies of approximately 80 animals, which are dominated by a single breeding female, the queen; this social system is highly unusual in mammals, but is similar to that commonly observed in bees and termites and is termed eusocial1.

 

Over the last decade further physiological peculiarities of naked mole-rat physiology have come to light:

Extreme Longevity – naked mole-rats live until 30 years of age, whereas the longevity of similarly sized mice is 2-3 years; moreover, naked mole-rats display sustained good health into old age2,3

Cancer Resistance – naked mole-rats do not spontaneously develop cancer4 and their cells are resistant to transformation

Insensitivity To Acid As A Noxious Stimulus – naked mole-rats respond normally to mechanical and thermal stimuli, but fail to perceive acid as noxious5

Hypoxia Resistance – naked mole-rat brain tissue can withstand sustained periods of hypoxia and even anoxia6,7

 

 

While such phenomena are of great interest there has been little work identifying their causes, although there is clearly much that could be learned from the naked mole-rat that could aid advances2. In 2014, scientists from the University of Cambridge Department of Pharmacology established the University of Cambridge Naked Mole-Rat Initiative (NMRI), which aims to bring together experts in different scientific areas with the overarching aim being to identify molecular explanations for the highly unusual physiology of this species. The majority of the work carried out by this initiative will be on established NMR cell lines.

An example of previous success in this area comes from a study by Dr Ewan St. John Smith, a founding member of the NMRI, which identified the molecular basis of naked mole-rat acid-insensitivity. It was shown that a variant in the voltage-gated sodium channel NaV1.7 is more greatly inhibited by acid in naked mole-rat pain-sensing neurones (nociceptors) compared to mouse: acid anaesthetises, rather than stimulates, naked mole-rat nociceptors8. This work thus demonstrates the power of comparative physiology: through using standard rodent models the role of voltage-gated sodium channels in the acid-pain pathway had not been demonstrated, but by taking advantage of the naked mole-rat’s natural adaptation to its environment we were able to identify an important function of NaV1.7.

More recently Dr Smith was part of a study that demonstrated that naked mole-rats are highly resistant to hypoxia and anoxia due to their cells being able to efficiently utilise fructose to power energy production during periods of low oxygen7. This work enhances understanding of how nerve cells can function in the absence of oxygen and might lead to work that uncovers novel treatments to prevent brain damage in stroke patients. Dr Smith’s lab have also recently identified appropriate housekeeping genes for the expression studies using naked mole-rat tissue9, and in a study led by Dr Matthew Mason’s lab in the Dept. of Physiology, Development and Neuroscience, an in depth anatomical description of the naked mole-rat’s peripheral auditory system was made10, which sheds light on the restricted hearing of naked mole-rats.

 

References:

1.         Jarvis, J.U. Science 212, 571–3 (1981).

2.         Schuhmacher, L.-N., Husson, Z. & Smith, E.S. Open Acc Anim Phys 137 (2015).

3.         Buffenstein, R. J Comp Physiol B 178, 439–45 (2008).

4.         Delaney, M.A., Nagy, L., Kinsel, M.J. & Treuting, P.M. Vet Pathol 50, 607–621 (2013).

5.         Park, T.J. et al. PLoS Biol 6, e13 (2008).

6.         Larson, J. & Park, T.J. Neurorep 20, 1634–1637 (2009).

7.         Park, T.J. et al. Science 356, 307–311 (2017).

8.         Smith, E.S.J. et al. Science 334, 1557–1560 (2011).

9.         Schuhmacher, L.-N. & Smith, E.S.J. Mol. Brain 9, 97 (2016).

10.       Mason, M.J., Cornwall, H.L. & Smith, E.S.J. PLOS ONE 11, e0167079 (2016).

 

Below you can read about the members of the NMRI, their expertise and current research interests:

University of Cambridge

Dr Ewan St. John Smith (Pharmacology)

NMRI role: PI

Research Interests: Hypoxia/hypercapnia insensitivity and cancer resistance

Expertise: Electrophysiology, molecular biology, cell culture, immunohistochemistry and behaviour

Podcasts: With Science, The Physiological Society and the Naked Scientist

 

Dr Walid T. Khaled (Pharmacology)

NMRI role: PI

Research Interests: Cancer development and heterogeneity

Expertise: Cancer biology, genetically engineered cancer models and genetic screens

 

Dr Laura Itzhaki (Pharmacology)

NMRI role: PI

Research Interests: Cancer resistance and protein homeostasis

Expertise: Protein folding and stability, cancer therapeutics

 

Dr Pentao Liu (Sanger Institute)

NMRI role: PI

Research Interests: Cancer and mouse development

Expertise: Pluripotent stem cell technology, genetics

 

Dr Matt Mason (PDN)

NMRI role: PI

Research Interests: Structure and function of the middle ear in subterranean mammals

Expertise: Anatomy, biology of hearing.

 

Dr Kosuke Yusa (Sanger Institute)

NMRI role: PI

Research Interests: Inducible pluripotent stem cells, genetic screens

Expertise: CRISPR screens, genetics

 

External Collaborators:

 

Dr John Apergis-Schoute (Neuroscience, Psychology and Behaviour, Leicester)

NMRI role: PI

Research Interests: Sleep/appetite regulation and hypoxia/hypercapnia insensitivity

Expertise: Behaviour, electrophysiology and immunohistochemistry

 

Dr Daniel Frankel (Chemical Engineering and Advanced Materials, Newcastle)

NMRI role: PI

Research Interests: Extracellular matrix proteins in cancer and chemotherapy resistance, biofilms

Expertise: Microfluidics, atomic force microscopy

 

Kenneth Rankin (Northern Institute for Cancer Research, Newcastle)

NMRI role: PI

Research Interests: Musculoskeletal oncology, matrix metalloproteinases, osteoarthritis

Expertise: Surgeon, functional analysis of novel genese

 

Postdoctoral staff:

Dr Zoé Husson (Pharmacology, Cambridge)

NMRI role: Research Associate (Smith lab)

Research interests: Mechanisms of hypoxia/hypercapnia resistance

Expertise: Electrophysiology, immunohistochemistry

 

Funding

We are grateful for the following support:

• EMBO Long-Term Fellowship – Dr Zoé Husson

• Isaac Newton Trust

• Cancer Research UK

 

Publications

Park, T. J., Reznick, J., Peterson, B. L., Blass, G., Omerbasic, D., Bennett, N.C. Kuich, P.H.J.L, Zasada, C., Browe, B.M., Hamann, W., Applegate, D.T., Radke, M.H., Kosten, T., Lutermann, H., Gavaghan, V., Eigenbrod, O., Bégay, V., Amoroso, V.G., Govind, V., Minshall, R.D., Smith, E.S., Larson, J., Gotthardt, M., Kempa, S. and Lewin, G.R. (2017) Fructose-driven glycolysis supports anoxia resistance in the naked mole-ratScience356, 307-311.

Schuhmacher, L. N. and Smith, E. S. (2016). Expression of acid-sensing ion channels and selection of reference genes in mouse and naked mole rat. Mol. Brain997.

Mason, M. J., Cornwall, H. L. and Smith, E. S. (2016). Ear Structures of the Naked Mole-Rat, Heterocephalus glaber, and Its Relatives (Rodentia: Bathyergidae). PLoS One, 11, e0167079.

Omerbasic, D.*, Smith, E. S.*, Moroni, M, Eigenbrod, O., Homfeld, J., Reznick, J., Bennett, N. C. Faulkes, C., Selbach, M, and Lewin, G. R. (2016).  Hypofunctional TrkA accounts for the absence of pain sensitization in the African naked mole-ratCell Rep.17, 748-758 (* = equal contribution).

Schuhmacher, L. N., Husson, Z. and Smith, E. S. (2015). The naked mole-rat as an animal model in biomedical research: current perspectives. Open Access Animal Physiology, 7, 137-48.