Professor Valerie O'Donnell

Professor Valerie O'Donnell

Director, Division of Infection and Immunity & Co-Director of Systems Immunity Research Institute

School of Medicine

Email:
o-donnellvb@cardiff.ac.uk
Telephone:
+44 (0)29 2068 7313
Location:
Tenovus Institute

Our research uses mass spectrometry to discover and characterise new lipids (fats) made by circulating vascular cells that regulate immune defence and blood clotting.

Recently we showed that human blood platelets generate a large number of oxidized phospholipids several of which help clotting factors in plasma work more effectively.  We also uncovered a new role for phospholipases in providing energy to the cell and how lipids in different people respond individually to aspirin (http://www.cardiff.ac.uk/news/view/264589-understanding-the-bodys-response-to-aspirin)

Our current research is focused on understanding the role of new lipids in vascular inflammation including cardiovascular disease, dementia and wound healing.  Some lipids we discovered are being developed as the basis of new treatments for bleeding excess. Other lipids we showed are anti-inflammatory are being developed as treatments for vascular inflammation, licensed to Complexa Inc, and with a  $62M Series C funding investment in 2016 (https://www.cardiff.ac.uk/news/view/910011-turning-lipids-research-into-new-drugs)

In 2016, the Wellcome Trust funded a £1.3M 5 yr initiative led by our group jointly with Babraham Institute, Cambridge, and University of California San Diego to fund continuation and further development of LIPID MAPS, the global online database and resource for lipid research (http://www.cardiff.ac.uk/news/view/380752-new-funding-boosts-lipidomics-research).

Research in our group is funded by grants from the European Research Council, Wellcome Trust, British Heart Foundation, Royal Society and Medical Research Council.

Education:

1993 PhD Bristol University, Biochemistry

1990 BSc, University of Dublin, Trinity College, Human Nutrition and Dietetics

Honours and awards

Royal Society Wolfson Research Merit Awardee (2017)

ERC Advanced Investigator (2015-)

Honorary Professor, Faculty of Medicine, University of the Republic, Montevideo, since 2008.

Marie Curie Excellence Award (EU), Brussels, March 2008

Wellcome Trust University Award, Cardiff University, 2002-2007

Iron Bolt Award, Gordon Research Conference on Oxygen Radicals, 2004

Wellcome Trust RCD Fellow, Cardiff University, 1999-2002

Parker B Francis Pulmonary Fellow, University of Alabama at Birmingham, 1997-1999

European Union Marie Curie Fellow, University of Berne, Switzerland, 1995-1996

Professional memberships

Fellow of the Learned Society of Wales, April 2015-

Fellow of the Royal Society of Biology, June 2013-

Committees and reviewing

-Member, Population and Systems Medicine Board, Medical Research Council, 2016-2018

-Deputy Chair Medical Research Council Non-Clinical Training and Career Development Panel Oct 2014-Mar 2016.

-Wellcome Trust, Member of Biomedical Resources Grant Committee (April 2015-)

-Wellcome Trust Peer Review College, Sept 2012-2015

-NISCHR Health Grants Panel, Welsh Assembly Government, July 2012 – July 2014

-Medical Research Council Non-Clinical Training and Career Development Panel Apr 2012-Mar 2014.

2007-2017

Since 2007 my group have discovered large numbers of lipids made by human platelets, neutrophils and monocytes, via the lipoxygenase and cyclooxygenase pathways. We have shown that these lipids can innate immunity including promoting blood clotting, immune signaling and antibacterial activities of leukocytes. They belong to families of enzymatically oxidized phospholipids (eoxPL), and their elevated generation is found in human thrombotic disease, while their deficiency leads to bleeding defects and protection against vascular inflammation. This work is done in collaboration with Prof Peter Collins and Dr Vince Jenkins (UHW).

  1. Lauder, SN, Allen-Redpath, K, Slatter, DA, Aldrovandi, M, O’Connor, A, Farewell, D, Percy, CL, Molhoek, JE, Rannikko, S, Tyrrell, VJ, Ferla, S, Milne, GL, Poole, AW, Thomas, CP, Obaji, S., Taylor, PR, Jones, SA, de Groot, PG, Urbanus, RT, Horkko S, Uderhardt, S, Ackermann, J, Jenkins, PV, Brancale, A, Kroenke, G, Collins, PW and O’Donnell, VB (2017) Networks of enzymatically oxidized membrane lipids support calcium - dependent coagulation factor binding to maintain hemostasis. Science Signaling Vol. 10, Issue 507, eaan2787, DOI: 10.1126/scisignal.aan2787
  2. O’Connor, A, Brasher, C, Slatter, DA, Meckelmann, SW, Hawksworth, JI, Allen, SM, O’Donnell, VB. (2017), LipidFinder, a computational workflow for discovery of lipids identifies new eicosanoid-phosphoinositides in platelets. J Clin Invest Insight 2(7):e91634. doi:10.1172/jci.insight.91634
  3. Slatter, DA, Aldrovandi, M, O’Connor, A, Allen, S, Brasher, C, Murphy, RC, Meckelmann, S, Ravi, S, Darley-Usmar, V and O’Donnell, VB. (2016) Mapping the human platelet lipidome reveals cytosolic phospholipase A2 as a regulator of mitochondrial bioenergetics during activation. Cell Metabolism 23, 930-934, with commentary by FitzGerald, GA, Human platelet lipidomics: variance, visualization, flux and fuel. 23, 757-759
  4. Hammond VJ, Morgan, AH, Thomas, CP, Brown, S, Freeman, BA, Lloyd, CM, Davies, J, Bush, A, Levonen, AL, Kansanen, E, Villacorta, L, Chen, YE, Porter, N, Garcia Diaz, YM, Schopfer, FJ & O’Donnell, VB (2012) Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis and activate peroxisome proliferator-activated receptor-g. J Biol Chem 287, 41651–41666.
  5. O’Donnell, VB, Murphy, RC. New families of bioactive oxidized phospholipids generated by immune cells: identification and signaling actions. (2012) Blood 120, 1985-1992
  6. Clark, SR, Guy, CJ., Scurr, MJ, Thomas, CP, Coles, B., Roberts, G, Eberl, M., Jones, SA, Topley, N, Kotceha, S. and O’Donnell, VB (2011) Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection” Blood 117, 2033-2043

1999-2007

On arriving in Cardiff, I defined with my colleagues how lipid oxidation mediated by vascular enzymes can control blood pressure both in vitro and in vivo. Main findings include showing how cellular lipoxygenases and cyclooxygenases catalytically consume nitric oxide resulting in vasoconstriction and how neutrophils patrol the vasculature maintaining blood pressure through dampening bacterial-induced inflammation.

  1. Morton, J., Coles, B., Wright, K., Gallimore, A., Morrow, JD, Terry, ES, Anning PB, Morgan, BP, Dioszeghy, V., Kuhn, H., Chaitidis, P, Hobbs, A., Jones, SA and O’Donnell, VB. (2008) “Circulating neutrophils maintain physiological blood pressure by suppressing bacteria and IFNg-dependent iNOS expression in the vasculature of healthy mice” Blood 111, 5187-94
  2. Anning, P.B, Coles, B., Wang, H., Morrow, J.D, Dey, S.K, Marnett, L.J. and O’Donnell, V.B. (2006) “Removal of nitric oxide is required for hypertensive and prothrombotic effects of COX-2 inhibition in vivo. Blood 108, 4059-4062
  3. Williams, P.C., Coffey, M.J., Coles, B., Sanchez, S., Morrow, J.D., Cockcroft, J.R., Lewis, M.J. and O’Donnell, V.B. “In vivo aspirin supplementation inhibits nitric oxide consumption by human platelets.” (2005) Blood 106, 2737-2743
  4. Coffey, M.J., Chumley, P.H., Coles, B., Natarajan, R., Thimmalapura, P., Nowell, M., Kühn, H., Lewis, M.J., Freeman, B.A. and O’Donnell, V.B. (2001) “Catalytic consumption of Nitric Oxide by 12/15-Lipoxygenase: Inhibition of Monocyte Soluble Guanylate Cyclase Activation.” Proc. Natl. Acad. Sci. USA 98, 8006-8011

1996-1999

While based at University of Alabama at Birmingham I worked with the Freeman lab to characterisedhow nitric oxide and lipid oxidation pathways intersect (published in JBC, Biochemistry), defining new biochemical routes to nitrolipid synthesis, and showing these lipids have potent anti-inflammatory actions. These studies contributed to a patent which is licenced to Complexa Inc and the lipids are now in Phase II trials for vascular inflammation.

  1. O’Donnell, V.B., Taylor, K.P., Parthasarathy, S., Kühn, H., Koesling, D., Friebe, A., Bloodsworth, A., Darley-Usmar, V.M. and Freeman, B.A. (1999) “15-Lipoxygenase catalytically consumes nitric oxide and impairs activation of guanylate cyclase” J. Biol. Chem 274, 20083-20091
  2. O’Donnell, V.B., Eiserich, J.P., Darley-Usmar, V.M., Chumley, P.H., Kirk, M., Barnes, S. and Freeman, B.A. (1999) Nitration of unsaturated lipid by nitric oxide derived reactive nitrogen species, peroxynitrite, nitrogen dioxide, nitrous acid and nitronium ion” Chem. Res. Toxicol. 12, 83-92
  3. Coles, B., Bloodsworth, A., Clark, S.R., Lewis, M.J., Cross, A.R., Freeman, B.A. and O’Donnell, V.B. (2002) “Nitrolinoleate inhibits multiple indices of neutrophil function” Circ. Res 91, 375-381 (Editorial, Freedman, J. “Nitrated lipids, defining their bioactivity” (2002) Circ. Res. 91, 371-372)
  4. Coles, B., Bloodsworth, A., Eiserich, J.P., Coffey, M.J., McLaughlin, R.M., Giddings, J.C., Lewis, M.J., Haslam, R.J., Freeman, B.A. and O’Donnell, V.B. (2002) “Nitrolinoleate inhibits platelet activation by attenuating calcium mobilization and inducing phosphorylation of vasodilator-stimulated phosphoprotein (VASP) through elevation of cAMP” J. Biol. Chem 277, 5832-5840

1990-1996

I studied at University of Berne, Switzerland on a Marie Curie Fellowship (1994-1996). I defined mechanisms of mitochondrial free radical generation. My PhD at University of Bristol (1990-1993) was focused on characterising the enzymatic action of iodonium compounds as flavoenzyme inhibitors that were in development as anti-inflammatory agents. I found that these are turnover dependent, irreversible inhibitors that form covalent adducts with flavin co-factors. These inhibitors represent some of the most widely used NADPH oxidase inhibitors still used today.

  1. O'Donnell, V.B., Smith, G.C.M. & Jones, O.T.G. (1994) "Involvement of phenyl radicals in iodonium compound inhibition of flavoenzymes". Molecular Pharmacology 46, 778-785
  2. O'Donnell, V.B., Tew, D.G., Jones, O.T.G., England, P.J. (1993) "Studies on the inhibitory mechanism of iodonium compounds with special reference to neutrophil NADPH oxidase." Biochem. J. 290, 1, 41-49.

LIPID MAPS Database and Resource funded by Cardiff-led funding from Wellcome Trust

In 2016, the Wellcome Trust funded a £1.3M 5 yr initiative led by our group jointly with Babraham Institute, Cambridge, and University of California San Diego to fund continuation and further development of LIPID MAPS, the global online database and resource for lipid research (http://www.cardiff.ac.uk/news/view/380752-new-funding-boosts-lipidomics-research).