Research Network for Metals in Medicine

 

 

Dr Paul Witting

Position: ARC Australian Research Fellow

Affiliation: Vascular Biology Group, Anzac Research Institute

Postal Address:
Anzac Research Institute
Hospital Road
Concord Repatriation General Hospital
Concord NSW, 2139
AUSTRALIA

Phone: +61 (02) 9767 9103
Fax: +61 (02) 9767 9101
Email: pwitting@anzac.edu.au
Webpage: http://www.anzac.edu.au


Research Profile

Dr Witting has a proven track-record relative to career stage, publishing over 50 (43 primary papers) papers in peer-reviewed journals with an average impact factor 4.5 and one international Patent. The applicant has maintained a goal to publish novel data with an emphasis on primary publications (>90% appear in international journals). Notably, one paper has been highlighted as a journal cover (FEBS Lett., 1995, 375, 45-49), a second paper (J. Clin. Invest., 1999, 104, 213-220) has attracted an editorial commentary and a third (Arterioscl. Thromb. Vasc. Biol., 2000, 20, 26e-33e) has been published in the American Heart Association journal Arteriosclerosis, Thrombosis and Vascular Biology (a high impacting journal in the field of vascular research). From his publications, seven are published in the Journal of Biological Chemistry and 7 appear in American Chemical Society journals. In the majority of his publications Witting is the first or senior author.

Current position - Dr Witting has recently moved from the Centre for Vascular Research to establish himself as an independent Senior Scientist in the Vascular Biology Group at the Anzac Research Institute (ARI) Concord Hospital. Formation of the Vascular Biology Group is a joint initiative between the ARI and the Department of Cardiology (Concord Hospital) and represents a new addition to the research collective of the Institute. This opportunity to act completely as an independent researcher represents a major advance in Dr Witting’s career. This voluntary relocation was a step designed to give Dr Witting an opportunity to work more closely with practicing Clinicians (eg., Cardiology Department of Concord Hospital) as he explores a role for haem protein derived oxidative stress in diseases associated with vascular dysfunction (eg., atherosclerosis and stroke).

Dr Witting received his doctorate in 1994 specialising in physical organic chemistry. His post-graduate studies have resulted in 6 peer-reviewed publications. In his first post-doctoral appointment at the Heart Research Institute Dr Witting studied mechanisms of lipoprotein lipid peroxidation, focusing on both identifying radical species that initiate this form of oxidation and developing inhibitors of these deleterious oxidants.

Key scientific achievements from these studies include: (a) developing a novel in vitro method for detecting efficient inhibitors of lipid peroxidation termed co-antioxidants. An international Patent now covers this intellectual property. (b) Screening and identifying a series of potent inhibitors using this method, and (c) investigations on the efficacy of these lead compounds in animal intervention studies in collaboration with a commercial partner (AstraZeneca, Pharmaceutics). These latter studies showed, for the first time, that the inhibitors identified through the screening process (a), are active in vivo, thereby establishing the usefulness and relevance of the novel method. As evidence of the impact of these achievements it is notable that several co-antioxidants are currently being tested further in the laboratory of Prof. Roland Stocker using animal models of atherosclerosis/restenosis. These significant endeavours demonstrate the applicant’s ability to focus his research to the field of biomedical research.

Dr Witting is a career researcher and is funded currently by an Australian Research Fellowship awarded through a National competitive process from the ARC. He gained this prestigious award while at the Centre for Vascular Research (University of New South Wales). Prior to the ARC Fellowship, Dr Witting held a National Heart Foundation Fellowship, which financed an overseas post-doctoral appointment in the Department of Biochemistry and Molecular Biology (University of British Columbia, Canada).


Selected Publications

  1. Witting P.K., Upston J.M., and Stocker R. Formation of a-Tocopheroxyl Radical Initiates Lipid Peroxidation in LDL Exposed to Horse Radish Peroxidase. Biochemistry 1997, 36, 1251-1258.
  2. Garner B., Witting P.K., Waldeck A.R., Christison J.K., Raftery M., and Stocker R. Oxidation of High Density Lipoproteins. I. Formation of methionine sulfoxide in apolipoprotein AI and AII is an early event accompanying lipid peroxidation and can be enhanced by a-tocopherol. J. Biol. Chem., 1998, 273, 6080-6087.
  3. Garner B.,Waldeck A.R., Witting P.K., Rye K.A., and Stocker R. Oxidation of High Density Lipoproteins. II. Evidence for direct reduction of lipid hydroperoxides by methionine residues of apolipoprotein AI and AII. J. Biol. Chem., 1998, 273, 6088-6094.
  4. Neuzil J., Upston J.M., Witting P.K., Scott K.F., and Stocker R. Secretary Phospholipase A2 and Lipoprotein Lipase Enhance 15-Lipoxygenase-induced Enzymic and Nonenzymic Lipid Peroxidation in Low Density Lipoprotein. Biochemistry 1998, 37, 9203-9210.
  5. Witting P.K., Willhite C.A., Davies M.J., and Stocker R. Oxidation of Low Density Lipoprotein by Metmyoglobin/H2O2: Involvement of a-tocopheroxyl radical then alkoxyl radicals derived from phosphatidycholine hydroperoxides upon depletion of vitamin E. Chem. Res. Toxicol., 1999, 12, 1173-1181.
  6. Witting P.K., Douglas D.J., and Mauk A.G. Reaction of Recombinant Human Myoglobin and H2O2: A role for the thiyl radical produced at cysteine 110? J. Biol. Chem., 2000, 275, 20391-20398.
  7. Witting P.K., Douglas D.J., and Mauk A.G. Reaction of Human Myoglobin and Nitric Oxide: Heme iron- or protein sulfhydryl (S)-nitrosation dependence on the absence or presence of oxygen. Free Radic. Biol. Med., 2000, 29, S77.
  8. Witting P.K., Douglas D. J., and Mauk A. G. Reaction of Human Myoglobin and Nitric oxide: Formation of heme iron- or sulfhydryl (S)-nitrosated protein dependence on the absence or presence of oxygen. J. Biol. Chem., 2001, 276, 3991-3998.
  9. Travascio P., Witting P.K., Mauk A.G., and Sen D. The Peroxidase Activity of a Hemin-DNA Oligonucleotide Complex: Free radical damage to specific guanine bases of DNA. J. Am. Chem. Soc., 2001, 123, 1337-1348.
  10. Witting P.K., and Mauk A.G. Reaction of Human Myoglobin and H2O2: Electron transfer between tyrosine phenoxyl radical and cysteine in human myoglobin yields a protein-thiyl radical. J. Biol. Chem., 2001, 276, 16540-16547.
  11. Witting P.K., Mauk A.G., Douglas D.J., and Stocker R. Reaction of Human Myoglobin and Peroxynitrite: Characterising biomarkers for myoglobin-derived oxidative stress. Biochem. Biophys. Res. Commun., 2001, 286, 352-356.
  12. Witting P.K., Travascio P., Sen D., and Mauk A.G. A DNA-oligonucleotide Hemin Complex Decomposes t-Butyl Hydroperoxide through a Homolytic Mechanism. Inorg. Chem., 2001, 40, 5017-5023.
  13. Mauk A.G., Hunter C.L., Witting P.K., Maurus R., and Brayer G.D. New Ligand Binding Options for Human and Engineered Horse Myoglobins. J. Inorg. Biochem., 2001, 86, S72.
  14. Witting P.K., Mauk A.G., and Lay P.A. Effect of the Tyr103Phe Point Mutation in Human Myoglobin on Reaction with H2O2: A Kinetic and steady-state analyses. Biochemistry 2002, 41, 11495-11503.
  15. Andriambeloson E., and Witting P.K. Chemical regulation of Nitric Oxide: A role for intracellular myoglobin? Redox Report 2002, 7, 131-136.


Facilities

The ARI is a relatively new Institute that is primarily committed to investigating the underlying processes associated with disease progression related to ageing. Research at the ARI is focused on the areas of Andrology, Biogerontology, Bone Biology and Neurobiology and provides a competitive and stimulating research environment equipped with the necessary facilities for cell culture, biochemical analyses of cell proteins, assessment of vascular function and nitric oxide production from cells, immuno-histochemistry, molecular biology and animal housing/husbandry for intervention-based studies. The addition of the Vascular Biology Group expands the range of research fields at the ARI and will strengthen links between the ARI and Concord Hospital through the close relationship of the Vascular Biology Group and the Cardiology Department. The opportunity for Dr Witting to work in collaboration with established researchers in the ARI and clinicians from Concord Hospital will further broaden his research potential.

International Linkages

Professor A. Grant Mauk, Department of Biochemistry and Molecular Biology (University of British Columbia, Vancouver, Canada). This collaboration has continued since the applicant spent 2 years (1999-2001) in Prof. Mauk’s lab as a Visiting Fellow. Studies performed in collaboration with Prof. Mauk have resulted in 8 publications three of which appear in the Journal of Biological research. Prof. Mauk has an established track-record in the field of electron transfer processes in haem proteins and associated haem protein (bio)chemistry. Through his established links with Prof. Mauk the applicant has access to laser flash-photolysis equipment for the analyses of rapid kinetic reactions as well as a wealth of experience in the field of recombinant protein chemistry including production of variant proteins through site-directed mutagenesis. Planned studies involving a plasma copper-protein (ceruloplasmin) will start in the early stages of 2004.