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Research Fellows Directory

Nicholas Dale

Professor Nicholas Dale

Research Fellow

Organisation

University of Warwick

Research summary

Carbon dioxide is the unavoidable by-product of cellular metabolism. Adult humans produce about 20 moles of carbon dioxide per day. Carbon dioxide readily combines with water to form bicarbonate and hydrogen ions. Because an increase of only 100 nM in the concentration of hydrogen ions in blood can prove fatal, the regulated excretion of carbon dioxide during breathing is an extremely important, life-preserving process. By studying the carbon dioxide-dependent regulation of breathing, I have discovered a new carbon dioxide-dependent signalling paradigm. Carbon dioxide binds to a membrane channel called connexin26 (Cx26) and causes it to open. This allows release of the signalling molecule, ATP, which then acts via specific receptors to effect cellular responses, and ultimately the adaptive regulation of breathing. My research encompasses understanding Cx26-mediated carbon dioxide signalling from the fundamental level of structural biology -how carbon dioxide interacts with the protein -to how Cx26 regulates breathing and other aspects of physiology. I plan to produce new X-ray crystal structures of Cx26 to directly visualize carbon dioxide binding, to elucidate how the chemical environment around the carbon dioxide-binding site permits interaction and how the conformation of Cx26 changes to permit opening of the channel. Carbon dioxide-dependent signalling via Cx26 may have roles in physiology beyond the control of breathing. Certain Cx26 mutations cause KID syndrome, a rare but devastating pathology, which involves a combination of deafness, visual impairment and skin abnormalities. I have found that two Cx26 mutations associated with KID syndrome abolish the carbon dioxide sensitivity of Cx26. I plan to develop a range of new genetic techniques for manipulating the expression of Cx26, or inducing the expression of mutant Cx26 variants involved in diseases, to establish causality between the signalling roles of Cx26 in normal physiology and pathology.

Grants awarded

The role of CO2 sensing mediated by connexin26 in health and disease

Scheme: Wolfson Research Merit Awards

Dates: May 2015 - Apr 2020

Value: £50,000