Professor Paul Thornalley
|
||
TITLEProfessor of Systems Biology and Deputy Head, Division of Metabolic and Vascular Health CONTACT
|
RESEARCH PROFILELeading a multi-disciplinary team working in the field of disease mechanisms - particularly the study of damage to the proteome by glycation, oxidation and nitration, related enzymatic countermeasures raised by transcription factor Nrf2 and antioxidant response element (ARE)-regulated expression and other metabolic dysfunction. A distinctive and pioneering expertise is glycation by the dicarbonyl metabolite methylglyoxal and prevention of this by the glyoxalase system. Diseases under current investigation are: vascular complications of diabetes, renal failure, ageing and glyoxalase 1-linked multidrug resistant tumours. Novel therapeutics development under current investigation are: glyoxalase 1 inducers, glyoxalase 1 inhibitors and Nrf2 activators. I have a particular interest in: (i) inducers of glyoxalase 1 for diabetic vascular disease and healthy ageing, and (ii) glyoxalase 1 inhibitors for glyoxalase 1-mediated multidrug resistant tumours. Novel diagnostics under investigation are: biomarkers for vascular and metabolic health, and healthy ageing. CONFERENCE Glyoxalase Centennial: 100 years of glyoxalase research and emergence of dicarbonyl stress, 27th to 29th November 2013, University of Warwick, Coventry, UK. Contact PJT for details. |
RESEARCH GROUPS |
BACKGROUNDMy PhD studies and initial post-doctoral research was on oxidative stress and free radical mediated processes in cellular and pharmacological processes. Since then I have worked for over 25 years on processes of protein glycation involved in the development of microvascular complications in diabetes, renal failure and ageing, publishing a total of 240 peer-reviewed articles and 160 conference papers with h-factor 57. I have also filed 7 patents. I have a career-long interest in protein glycation by physiological dicarbonyl compounds ‒ particularly methylglyoxal (MG) ‒ and its suppression in physiological systems by the glyoxalase system. MG is now viewed as one of the most important precursors of advanced glycation endproducts (AGEs) in physiological systems and causes of spontaneous modifications to the proteome. In initial studies, my team developed and published biochemical methods for characterising MG metabolism by the glyoxalase system: activity, protein, genotype measurements of glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2); concentrations of metabolites MG, S-D-lactoylglutathione and D-lactate; molecular characteristics of human Glo1 and Glo2; and prototype cell permeable Glo1 inhibitor. These remain standard reference methods. I pioneered studies on the link of increased formation of MG in diabetes and the link to microvascular disease ‒ now viewed as important dysfunctional biochemical pathway linked to diabetic complications. I organised the first international symposium on 'Glyoxalase in Health and Disease' in 1992. I led studies on the mechanism of protein glycation by dicarbonyl compounds, identifying the major adducts formed ‒ arginine-derived hydroimidazolones. I developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for comprehensive quantitative screening of protein damage by glycation, oxidation and nitration ‒ providing for the first time a near complete profile of protein damage in diabetes, renal failure and other diseases. Thereby I discovered the widespread occurrence of endogenous dicarbonyl glycation of both cellular and extracellular proteins, export of proteolytic debris of dicarbonyl modified proteins from cells ‒ 'glycation free adducts' ‒ into plasma and other body fluids and efficient renal clearance and excretion of glycation free adducts in urine. I found profound plasma accumulation of glycation free adducts in diabetes and renal failure and identified glycation free adducts as the major form by which the body excretes protein glycation damage. Dialysis clears the same products in renal replacement therapy. I introduced the concepts of 'dicarbonyl proteome' and 'enzymatic defence against glycation'. The dicarbonyl proteome are proteins susceptible to functional impairment by dicarbonyl glycation. Important examples are type IV collagen (modification leading to endothelial cell anoikis) and cytochrome c1 (modification linked to increased reactive oxygen species formation). The enzymatic defence against glycation are enzymes protective against glycation damage. Glo1 is a key member of the anti-glycation defence ‒ together with fructosamine 3-phosphokinase and aldoketo reductases. I organised the first international meeting on this topic in 2003. I have collaborated widely with leading international research teams on vascular complications of diabetes, renal failure, arthritis and ageing to disclose the role of dicarbonyl glycation and Glo1 in disease processes and ageing. For example, reporting recently the increased lifespan of Caenorhabditis elegans achieved by overexpression of Glo1 and decreased lifespan by Glo1 silencing. Other studies have revealed: down-regulation of Glo1 by activation of the receptor for AGEs (RAGE) and increased dicarbonyl tissue injury in arthritis and other inflammatory disorders; and importance of Glo1 in neurological disorders ‒ further research areas to be fully explored for clinical benefit. Other recent achievements and activities are: (i) I led studies on high dose thiamine therapy for the prevention of diabetic nephropathy ‒ an intervention decreasing MG formation in diabetes. I discovered tissue-specific thiamine deficiency in experimental and clinical diabetes. I designed, coordinated and reported the first pilot intervention trial of high dose thiamine therapy in type 2 diabetic patients with early stage nephropathy. Thiamine therapy reversed early stage nephropathy and improved renal function in all patients treated. (ii) Collaborative research revealed that MG is the precursor of major endogenous DNA damage adducts (imidazopurinones) and the Glo1 gene is amplified in ca. 10% of human tumours conferring associated multidrug resistance. (iii) I and my colleague, Dr Naila Rabbani, are co-founding editors of the first peer-review journal for glycation research ‒ Amino Acids-Glycation (Springer). Dr Naila Rabbani and I currently co-direct our research team recognised as an international authority and research activity hub on protein damage in human disease, collaborating with leading international outreach partners. |
CURRENT RESEARCH PROJECTS
|
SELECTED PUBLICATIONS
|
|
|
RESEARCH DEGREES SUPERVISED
|
|
Update My Profile on the Warwick eRA Portal
You can Track My Proposals here |
My Profile last updated: 17/05/2013 |
