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Professor Nicholas Dale

Ted Pridgeon Professor in Neuroscience

Email: N.E.Dale@warwick.ac.uk

Ehone: 024 765 23729

Office: IBRB1.10

 Dale webpage


Research Clusters

Neuroscience

Quantitative, Systems & Engineering Biology


Vacancies and Opportunities

For PhD and postdoctoral opportunities, and interest in potential collaborations, please contact me at the above email address.


Research Interests

My group investigates fundamental mechanisms of signalling and communication in the nervous system and how these contribute to neural function and behaviour.

One of our current areas of interest is signalling mediated by CO2: what is the molecular mechanism of CO2 detection; how do levels of CO2 vary in the brain; which cells respond to CO2; what physiological processes are directly CO2 sensitive; and can we link defects of CO2-sensing to human disease?

A second area of focus is epilepsy. We wish to understand how seizures affect important nuclei in the brainstem that control breathing and the heart and whether repeated seizures cause long term changes to these circuits that could contribute to the risk of sudden unexpected death in epilepsy (SUDEP). Recently we have become interested in signalling mediated by the amino acid L-aspartate and a possible link to epilepsy.

A third area of focus is creation of new sensors to measure signalling molecules that are important for physiology in real time. While we have a long track record of creating electrochemical sensors, we are now increasingly modifying proteins to create genetically encoded sensors that can perform these measurements with greater precision and sensitivity.

Research: Technical Summary

Connexin-mediated CO2 signalling: from structural biology to function

Canonically, connexins form gap junctions that allow the passage of ions and small molecules between cells. However, they can also act as plasma membrane channels. We discovered that a small subset of beta connexins (Cx26, Cx30 and Cx32) are directly sensitive to CO2 -the plasma membrane channels of these connexins open to increases in CO2. We have shown that this occurs via a carbamylation mechanism and that the CO2 sensitivity of Cx26 contributes significantly to the control of breathing. Our focus is on further understanding (via cryoEM, with Prof Alex Cameron) the structural biology of how CO2 causes conformational change in these connexins and elucidating further physiological functions of connexin mediated CO signalling such as hypercapnic arousal reflexes (with Prof Mark Wall). We are also exploiting evolution of connexins to devise chimaeric modified connexin subunits that can coassemble with endogenously expressed connexins to remove CO2 sensitivity very selectively allowing us to further probe physiological function.

L-Aspartate signalling

We developed an electrochemical biosensor for L-Asp which has allowed us to study in real time L-Asp release in the nervous system. We wish to identify the neurons that release it, the key molecular components involved in its release and what function L-Asp may be serving in the brain. We have found evidence for a link between altered L-Asp signalling and epilepsy. As anti-seizure drugs are poorly effective in about 30% of people with epilepsy, our research could suggest new ways to develop drugs to control seizures.

Sensor development

We have more than 20 years of experience in developing electrochemical biosensors for neurochemicals. Our biosensor for L-Asp is the latest example of this. However, we are now pursuing a new approach: using molecular biology to modify natural receptors to create fluorescent reporters for molecules of interest. These have the advantage of being able to be expressed under genetic control and provide very precise and sensitive measurements at a cellular level.

Publications

For a full list of publications, see WRAP

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Biography

  • Ted Pridgeon Professor of Neuroscience, School of Life Sciences, University of Warwick (2000- )
  • Professor of Neuroscience, School of Biomedical Sciences, University of St Andrews (1999-2000)
  • Reader of Neuroscience, School of Biomedical Sciences, University of St Andrews (1997- 1999)
  • Royal Society Locke Research Fellow and Reader of Neuroscience, School of Biological & Medical Sciences, University of St Andrews (1995-1997)
  • Royal Society Locke Research Fellow, School of Biological Sciences, University of Bristol (1992-1995)
  • Royal Society 1983 University Research Fellow, School of Biological Sciences, University of Bristol (1989-1992)
  • Howard Hughes Medical Institute, Columbia University, New York. (1986-1989)