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Prof. Chris Cooper

Research Themes

1     Oxygen delivery (haem proteins, oxidative stress and blood substitutes)

This work is a part of our interdisciplinary collaborations within the Centre for Radicals and Oxidative StresS (CROSS).

Haemoglobin and myoglobin are the respiratory proteins responsible for the delivery of oxygen from the lungs to cytochrome oxidase in the mitochondria. The normal redox state of haemoglobin and myoglobin is ferrous iron (Fe2+), which will reversibly bind oxygen to form a stable oxy complex (oxyhaemoglobin). However, the oxy complex has the potential to autoxidise to form the ferric (met) haemoglobin. Methaemoglobin (FeIII) can react with peroxides to form ferryl iron (FeIV) and a protein-bound radical. Redox cycling between the ferric and ferryl forms of haem proteins can initiate lipid peroxidation and other free radical mediated reactions.

There are several clinical conditions where the globin ferric/ferryl redox cycle may become pathologically relevant. These include ischaemia and reperfusion, where ferryl myoglobin may help initiate myocardial injury. In the brain ferryl haemoglobin may damage arteries in subarachnoid haemorrhage and in stroke the modified haemoglobin has the potential to cross the blood brain barrier. In addition any situation where haemolysis occurs removes haemoglobin from within the protective environment of the red blood cell membrane and therefore unleashes its potential for initiating free radical damage. Such situations clinically include sickle cell or haemolytic anaemia and even atherosclerosis.

In order to study the clinical effects in more detail we have focused on the two main conditions where there are high level of ferric haem proteins outside the cell: rhabdomyolysis (myoglobin) and the use of haemoglobin based blood substitutes (haemoglobin).

We have recently used these ideas to design modified haemoglobins that we hope to have less toxic side effects when used clinically as artificial blood substitutes.

Selected recent publications

  1. Reeder, B. J., Grey, M., Silaghi-Dumitrescu, R. L., Svistunenko, D. A., Bulow, L., Cooper, C. E. and Wilson, M. T. (2008) Tyrosine residues as redox cofactors in human hemoglobin: Implications for engineering non toxic blood substitutes. J. Biol. Chem. In press

  2. Cooper, C. E. , Silaghi-Dumitrescu, R. L., Rukengwa, M., Alayash, A. I., and Buehler, P. W. (2008) Peroxidase activity of hemoglobin towards ascorbate and urate: a synergistic protective strategy against toxicity of hemoglobin-based oxygen carriers (HBOC) Biochim. et Biophys. Acta 1784 1415-1420

  3. Svistunenko, D.A., Reeder, B.J., Wankasi, M.M., Silaghi-Dumitrescu, R.L., Cooper, C.E., Rinaldo, S., Cutruzzola, F. and Wilson, M.T. (2007) Reaction of Aplysia limacina metmyoglobin with hydrogen peroxide Dalton Trans. 840-850

  4. Silaghi-Dumitrescu, R., Reeder, B.J., Nicholls, P., Cooper, C.E. and Wilson, M.T. (2007) Ferryl haem protonation gates peroxidatic reactivity in globins. Biochem. J. 403, 391-395

  5. Dunne, J., Caron, A., Menu, P., Alayash, A. I., Buehler, P. W., Wilson, M. T., Silaghi-Dumitrescu, R., Faivre, B. and Cooper, C. E. (2006) Ascorbate removes key precursors to oxidative damage by cell-free haemoglobin in vitro and in vivo, Biochem J. 399, 513-524.

  6. Vollaard, N. B., Cooper, C. E. and Shearman, J. P. (2006) Exercise-induced oxidative stress in overload training and tapering, Med. Sci. Sports Exerc. 38, 1335-41.

  7. Vollaard, N.B.J., Reeder, B.J., Shearman, J.P., Menu, P., Wilson, M.T. and Cooper, C.E. (2005) A new sensitive assay reveals that hemoglobin is oxidatively modified in vivo Free Rad. Biol. Med. 39, 1216-1228

  8. Vollaard, N.B.J., Shearman, J.P. and Cooper, C.E. (2005) Exercise-Induced Oxidative Stress: Myths, Realities and Physiological Relevance. Sports Med. 35, 1045-1062

  9. Silaghi-Dunitrescu, R. and Cooper, C.E. Transient species involved in catalytic dioxygen/peroxide activation by hemoproteins: possible involvement of protonated compound I species (2005) Dalton Trans. 21, 3477-3482.

  10. Cooper, C.E., Jurd, M., Nicholls, P., Wankasi, M.M., Svistunenko, D.A., Reeder, B.J. and Wilson, M.T. (2005) On the formation, nature, stability and biological relevance of the primary reaction intermediates of myoglobins with hydrogen peroxide Dalton Trans. 21, 3483 – 3488.

Recent patents

  1. C.E. Cooper, B. Reeder and M.T. Wilson GB 0712683.2 Improvements Relating to Oxygen-Carrying Proteins (1)

  2. C.E. Cooper, B. Reeder and M.T. Wilson GB 0712685.7 Improvements Relating to Oxygen-Carrying Proteins (2)

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2     Oxygen consumption (cytochrome oxidase, nitric oxide and mitochondria)

Cytochrome oxidase is the terminal electron acceptor of the mitochondrial electron transport chain and responsible for over 95% of oxygen consumption in the body. We are currently studying:

  1. The control of oxygen consumption by this enzyme in vitro and in vivo
  2. The role of possible pathophysiological inhibitors, especially the intercellular messenger nitric oxide

Key to this work is the development of mathematical models of oxygen consumption by cytochrome oxidase in vitro and in vivo.

Selected recent publications

  1. Cooper, C. E. and Brown, G. C. (2008) The inhibition of mitochondrial cytochrome oxidase by the gases carbon monoxide, nitric oxide, hydrogen cyanide and hydrogen sulfide: chemical mechanism and physiological significance. J. Bioenerg. Bimemb. In press

  2. Banaji, M., Mallett, A., Elwell, C. E., Nicholls, P. and Cooper, C. E. (2008) A model of brain irculation and metabolism: NIRS signal changes during physiological challenges PLOS Computational Biology In press

  3. Cooper, C. E. Mason, M. G., Nicholls, P. (2008) A dynamic model of nitric oxide inhibition of mitochondrial cytochrome c oxidase, Biochim. et Biophys. Acta, 1777, 867-876

  4. Mason, M.G., Holladay, R. S., Nicholls, Shepherd, M. and Cooper, C. E. (2008) A quantitative approach to nitric oxide inhibition of terminal oxidases of the respiratory chain, Methods in Enzymology 437, 135-159.

  5. Tachtsidis, I., Tisdall, M., Leung, T.S., Cooper, C.E., Delpy, D.T., Smith, M. and Elwell, C.E. (2007) Investigation of in-vivo measurement of cerebral cytochrome-c-oxidase redox changes using near-infrared spectroscopy in patients with orthostatic hypotension. Physiol. Meas. 28, 199-211

  6. Cooper, C. E and Giulivi, C., (2007) Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology, Am. J. Physiol. Cell Physiol. 292, C1993-C2003.

  7. Mason, M. G., Nicholls, P., Wilson, M. T. and Cooper, C. E. (2006) Nitric oxide inhibition of respiration involves both competitive (heme) and noncompetitive (copper) binding to cytochrome c oxidase, Proc. Natl. Acad. Sci. U S A. 103, 708-713.

  8. Giulivi, C., Kato, K. and Cooper, C. E. (2006) Nitric oxide regulation of mitochondrial oxygen consumption I: cellular physiology, Am. J. Physiol. Cell Physiol. 291, C1225-C1231

  9. Svistunenko, D.A., Wilson, M.T. and Cooper, C.E. (2004) Tryptophan or tyrosine? On the nature of the amino acid radical formed following hydrogen peroxide treatment of cytochrome c oxidase Biochim. Biophys. Acta 1655, 1655, 372-380.

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RESEARCH TOOLS

1     Optical Methods (Near infrared spectroscopy – NIRS)

This work is part of our interdisciplinary collaborations within the Medical Optics Group.

Near infrared spectroscopy (NIRS) is a technique that can probe the brain non-invasively. It utilises the fact that in the wavelength region from 650 - 1000nm there is relatively little absorbance of light by tissue. Light of these wavelengths can therefore interrogate the whole brain or muscle. Although the light exiting the tissue will be multiply scattered, it will still contain information about the concentration of the chromophores in this region. These are principally water, deoxyhaemoglobin (Hb), oxyhaemoglobin (HbO2), and cytochrome oxidase (Cyt).

Click here for an introduction to NIRS.

Our current NIRS studies have a number of different threads:

  1. The development of new methods, particularly with regards to mitochondrial cytochrome oxidase measurements (in collaboration with Professor Clare Elwell in the Biomedical Optics Research Laboratory at UCL)

  2. Using NIRS to improve sports performance (in collaboration with Dr. Marco Cardinale at the British Olympic Association)

  3. Monitoring of adult brain injury (in collaboration with Dr. Martin Smith at the Institute of Neurology, London)

  4. Monitoring visual stress in migraine (in collaboration with Professor Arnold Wilkins in the Department of Psychology at Essex)

Selected recent publications

  1. Cooper, C. E., Sharpe, M. A., Mason, M. G. and Nicholls, P. (2009) Steady state redox levels in cytochrome oxidase: relevance for in vivo near infrared spectroscopy (NIRS) Adv Exp Med Biol 645, in press

  2. Cooper, C. E., Cope, M., Elwell, C. E. and Delpy, D. T. (2009) Bicuculline-induced seizures: a challenge for optical and biochemical modeling of the cytochrome oxidase CuA NIRS signal Adv Exp Med Biol 645, in press

  3. Banaji, M., Mallett, A., Elwell, C. E., Nicholls, P. and Cooper, C. E. (2008) A model of brain circulation and metabolism: NIRS signal changes during physiological challenges PLOS Computational Biology In press

  4. Tachtsidis, I., Tisdall, M., Leung, T.S., Cooper, C.E., Delpy, D.T., Smith, M. and Elwell, C.E. (2007) Investigation of in-vivo measurement of cerebral cytochrome-c-oxidase redox changes using near-infrared spectroscopy in patients with orthostatic hypotension. Physiol. Meas. 28, 199-211

  5. Griffin, M., Prior, D., Cooper, C. E., Wilkins, A. J. and Elwell, C. E. (2006) Near infrared spectroscopy as a noninvasive assessment of cortical abnormality in migraine?, Adv Exp Med Biol. 578, 203-208.

  6. Cooper, C. E., Blannin, M., Hall, C. and Griffin, M. (2006) NIRS-detected changes in the arm during mental rehearsal of physical activity (imaginary exercise), Adv Exp Med Biol. 578, 191-196.

  7. Cooper, C. E., Pryor, D., Hall, C. and Griffin, M. (2006) NIRS-detected changes in the motor cortex during mental rehearsal of physical activity (imaginary exercise), Adv Exp Med Biol. 578, 185-190.

  8. Myers, D. E., Cooper, C. E., Beilman, G. J., Mowlem, J. D., Anderson, L. D., Seifert, R. P. and Ortner, J. P. (2006) A wide gap second derivative NIR spectroscopic method for measuring tissue hemoglobin oxygen saturation, Adv Exp Med Biol. 578, 217-222.

  9. Myers, D.E., Anderson, L.D., Seifert, R.P., Ortner, J.P., Cooper, C.E. , Beilman, G.J., and Mowlem, J.D. (2005) Noninvasive method for measuring local hemoglobin oxygen saturation in tissue using wide gap second derivative near-infrared spectroscopy. J. Biomed. Optics 10, 034017 (18 pages)

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2      Magnetic Methods (Electron Paramagnetic Resonance - EPR)

This work uses the facilities of the University of Essex Biomedical EPR facility

Electron paramagnetic resonance (EPR) spectroscopy is a technique for detecting unpaired electrons. In biological systems it has been used extensively for the study of free radicals and transition metals (especially iron and copper).

We use EPR to look at:

  1. The mechanism and control of free radical production by metalloproteins in vitro
  2. The role of free radicals, especially nitric oxide, in the whole organism in health and disease

Click here for an introduction to EPR

Selected recent publications

  1. Reeder, B. J., Grey, M., Silaghi-Dumitrescu, R. L., Svistunenko, D. A., Bulow, L., Cooper, C. E. and Wilson, M. T. (2008) Tyrosine residues as redox cofactors in human hemoglobin: Implications for engineering non toxic blood substitutes. J. Biol. Chem. In press

  2. Pipirou, Z., Bottrill, A. R., Svistunenko, D. A., Efimov, I., Basran, J., Mistry, S. C., Cooper, C. E., and Raven, E. L. (2007) The reactivity of heme in biological systems: autocatalytic formation of both tyrosine-heme and tryptophan-heme covalent links in a single protein architecture. Biochemistry, 46, 13269-13278

  3. Svistunenko, D.A., Reeder, B.J., Wankasi, M.M., Silaghi-Dumitrescu, R.L., Cooper, C.E., Rinaldo, S., Cutruzzola, F. and Wilson, M.T. (2007) Reaction of Aplysia limacina metmyoglobin with hydrogen peroxide Dalton Trans. 840-850

  4. Svistunenko, D. A., Davies, N., Brealey, D., Singer, M. and Cooper, C. E. (2006) Mitochondrial dysfunction in patients with severe sepsis: an EPR interrogation of individual respiratory chain components, Biochim. Biophys. Acta. 1757, 262-272.

  5. Dunne, J., Caron, A., Menu, P., Alayash, A. I., Buehler, P. W., Wilson, M. T., Silaghi-Dumitrescu, R., Faivre, B. and Cooper, C. E. (2006) Ascorbate removes key precursors to oxidative damage by cell-free haemoglobin in vitro and in vivo, Biochem J. 399, 513-524.

  6. Davies, N.A., Brealey, D.A., Stidwill, R., Singer, M., Svistunenko, D.A. and Cooper, C.E. (2005) Nitrosyl heme production compared in endotoxemic and hemorraghic shock. Free Rad. Biol. Med. 38, 41-49.

  7. Silkstone, G.G., Cooper, C.E. Svistunenko, D.A. and Wilson, M.T. (2005) EPR and Optical Spectroscopic Studies of Met80X Mutants of Yeast Ferricytochrome c. Models for Intermediates in the Alkaline Transition. J. Amer. Chem. Soc. 127, 92-99.

  8. Borrelly, G.P., Blindauer, C.A., Schmid, R., Butler, C.S., Cooper, C.E., Harvey, I., Sadler, P.J., Robinson, N.J. (2004) Novel copper site in a cyanobacterial metallochaperone. Biochem J. 378, 293-297.

  9. Vanin, A. F., Svistunenko, D. A., Mikoyan, V. D., Serezhenkov, V. A., Fryer, M. J., Baker, N. R. and Cooper, C. E. (2004) Endogenous superoxide production and the nitrite/nitrate ratio control the concentration of bioavailable free nitric oxide in leaves. J. Biol. Chem 279, 24100-24107.

  10. Svistunenko, D.A. and Cooper, C.E. (2004) A new method of identifying the site of tyrosyl radicals in proteins. Biophys J 87, 582-95.

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Contact address:

Prof Chris Cooper

Dept of Biological Sciences

University of Essex

Wivenhoe Park

Colchester CO4 3SQ

tel +44  (0)1206 872752
fax +44 (0) 1206 872592
email:  ccooper

(non-University users please  prefix 'ccooper' to the usual University address '@essex.ac.uk')

 

 

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