• Professor Paul J Thornalley Professor of Metabolic Biochemistry & Systems Biology	Dr Naila Rabbani Associate Professor of Experimental Systems Biology

Prof Paul J Thornalley and Dr Naila Rabbani co-direct the Protein Damage & Systems Biology Group in the Clinical Sciences Research Institute. They lead a team of

• 3 post-doctoral researchers

• 4 PhD students

• 2 technicians

In investigations of protein damage and anti-stress genes responses that protect against it in studies of vascular complications of diabetes, obesity, renal failure, neurological disorders and ageing. The team collaborates with other research teams in Systems Biology Centre and Departments of Chemistry, Biological Sciences, Statistics and Engineering in the University and clinical investigators in the University Hospital of Coventry and Warwickshire. The team is linked to Warwickshire Institute for Diabetes, Endocrinology & Metabolism (WISDEM), Warwick Centre for Analytical Sciences and clinical teams at the University Hospital of Coventry & Warwickshire (UHCW) and elsewhere. Many external collaborations with research teams in universities and companies nationally and internationally are also on-going.

Academic PA

Research profile

Protein Damage & Systems Biology are a multi-disciplinary group, working in the field of disease mechanisms - particularly in the study of damage to the proteome by glycation, oxidation and nitration, related enzymatic countermeasures and other metabolic dysfunctions.

Diseases under current investigation are:

• vascular complications of diabetes
• renal failure
• ageing

Therapeutic problems under current investigation are:

• high dose thiamine therapy for the prevention of diabetic nephropathy
• dialysis renal replacement therapy
• multi-drug resistance in cancer chemotherapy

Research interests are covered in more detail in the Research Interests section.

Funding

The group receives funding from the BBSRC, Wellcome Trust, British Heart Foundation, Diabetes UK, European Union, British Council (Prime Minister's Initiative-2), and other sources.

Major areas of research interest

• Dysfunctional Lipoprotein Metabolism in Obesity & Diabetes - Studies of hotspot sites of lipoprotein damage in vivo, change in lipoprotein functionality, risk of atherosclerosis and lipoprotein systems modelling in diabetes.

• Thiamine Metabolism & Therapy in Diabetes - Disturbance of thiamine metabolism in diabetes and high dose thiamine supplementation for the prevention of vascular disease in diabetes. Systems modelling of the disturbance in thiamine metabolism in diabetes and obesity.
• Anti-Stress Gene Responses - Studies of genomic and pharmacological regulation of gene expression via transcription factor NRF2 protective against chronic disease development and ageing. Systems modelling of the NRF2 - Anti-Stress gene response.

• Multidrug Resistance in Cancer Chemotherapy - Overexpression of glyoxalase I in innate and acquired multidrug resistance in cancer chemotherapy. Metabolomics and signalling in response to DNA damage.
• Biomedical Proteomics: Protein Damage & Proteolytic Debris -Studies of protein damage in mechanisms of chronic disease particularly vascular complications of diabetes, obesity, renal failure, neurological disorders and ageing. Quantitation of protein damage by mass spectrometry (stable isotopic dilution analysis and quantitative proteomics). Bioinformatics prediction of sites of protein damage. Systems modelling of physiological kinetics of protein damage and repair, replacement and proteolysis of damaged proteins.

Current research projects

Protein damage research

• Analysis of protein damage by glycation, oxidation and nitration in diet, plasma and urine
• BIOmarkers of Robustness of Metabolic Homeostasis for Nutrigenomics-derived Health BIOCLAIMS Made on Food (BIOCLAIMS) -EU FP7 research network
• Hotspot glycation of apolipoprotein B100 in LDL - importance in dyslipidaemia and atherosclerosis in diabetes and ageing
• Hotspot glycation of apolipoprotein A-1in HDL - importance in dyslipidaemia and atherosclerosis in diabetes and ageing

Anti-stress gene response research

• Dietary activators of antioxidant response element-linked gene expression for good vascular health
• Anti-stress gene response in cell and tissue ageing: role of transcription factor NF-E2-related factor-2 and effect on dietary activators

Thiamine research

• High dose thiamine therapy for regression of microalbuminuria in patients with type 2 diabetes
• Mechanism of increased renal clearance of thiamine in hyperglycaemia associated with diabetes and link to risk of vascular complications of diabetes
• Epidemiological cross-sectional study on B-vitamin acid status in South-East Asian diabetic patients
• Role of circulating advanced glycation end products (AGEs) in diabetic nephropathy: Effect of Benfotiamine intervention

Research team

Co-Director

• Dr Naila Rabbani (previously Naila Ahmed) - Associate Professor in Experimental Systems Biology.

Post-Doctoral Research Assistants

• Dr Mingzhan Xue - Dietary activators of antioxidant response element-linked gene expression for good vascular health (cellular and moecular biology)
• Dr Lisa Godfrey - Functional impairment of HDL by dicarbonyl glycation in glucose intolerance, obesity and type-2 diabetes - link to cardiovascular disease.
• Dr Hiroshi Momiji - (with David Rand, Warwick Systems Biology, and Guy Barker, Warwick HRI) Mathematical modelling of the antistress gene response

PhD Students

• Mr James Larkin - Mechanism of increased renal clearance of thiamine in hyperglycaemia associated with diabetes
•  Miss Fang Zhang - Mechanism thiamine deficiency in microvascular complications of diabetes
• Miss Sahar Waris - Preparation and measurement of dicarbonyl glycation adducts of deoxyguanosine in diabetes and glyoxalase 1-linked multidrug resistant tumours
• Dr Zehra Irshad - Dicarbonyl protein damage in vascular endothelial cells in hyperglycaemia associated with diabetes
• Miss Florence Hariton - Anti-stress gene response in cell and tissue ageing

MSc Student

• Usman Ahmed 

Technician

• Dr Muhammad Maqsud Anwar - Mass spectrometry and proteomics

Recent publications

2011

Journals

• Rabbani, N. and Thornalley, P.J. (2011) Protein damage in diabetes and uremia – identifying hotspots of proteome damage where minimal modification is amplified to marked pathophysiological effect. Free Radical Research 45, 89 – 100. 

• Kurz, A., Rabbani, N., Walter, M., Bonin, M., Thornalley, P.J., Auburger, G. and Gispert, S. (2011) Alpha-synuclein deficiency leads to increased glyoxalase I expression and glycation stress. Cell and Molecular Life Sci. 68, 721 – 733.

• Rabbani, N. and Thornalley, P.J. (2011) Glycation research in Amino Acids – a place to call home. Amino Acids, in press. in press. 

• Rabbani, N. and Thornalley, P.J. (2011) Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino acids, in press. 

• Murphy, M.P., Holmgren, Nils-Göran Larsson, A., Halliwell, B., Chang, C.J., Kalyanaraman, B., Rhee, S.G., Thornalley, P.J., Partridge, L., Gems, D., Nyström, T., Belousov, V., Schumacker, P.T. and Winterbourn, C.C. (2011) Unravelling the Biological Roles of Reactive Oxygen Species. Cell Metabolism, in press. 

• Kihm, L.P., Müller-Krebs, S., Klein, J., Ehrlich, G., Mertes, L., Gross, M.-L., Adaikalakoteswari, A. Thornalley, P.J. Hammes, H.-P., Nawroth, P., Zeier, M. and Schwenger, V. (2011) Benfotiamine Prevents Peritoneal Damage and Protects the Remnant Kidney in a PD Model in Uremic Rats. J Amer Soc Nephrol., in press. 

• Rabbani, N. and Thornalley, P.J. (2011) The glyoxalase system – from microbial metabolism, through ageing to human disease and multidrug resistance. Seminars in Cell and Developmental Biology, in press. 

• Xue, M., Rabbani, N. and Thornalley, P.J. (2011) Glyoxalase in ageing. Seminars in Cell and Developmental Biology, in press.

• Rabbani, N. and Thornalley, P.J. (2011) Glyoxalase in tumourigenesis and multidrug resistance. Seminars in Cell and Developmental Biology, in press.

• Rabbani, N. and Thornalley, P.J. (2011) Glyoxalase in diabetes and vascular disease. Seminars in Cell and Developmental Biology, in press. 

• Rabbani, N., Adaikalakoteswari, A., Rossing, K., Rossing, P., Tarnow, L., Parving, H.-H. and Thornalley, P.J. (2011) Effect of Irbesartan treatment on plasma and urinary protein glycation, oxidation and nitration markers in patients with type 2 diabetes and microalbuminuria. Amino Acids.  

• Rabbani, N. and Thornalley, P.J. (2011) Emerging role of thiamine therapy for prevention and treatment of early stage diabetic nephropathy. Diabetes, Obesity and Metabolism.

Chapters in books

• Thornalley, P.J. and Rabbani, N. (2011) Thiamine in diabetic renal disease – dietary insufficiency, renal washout, anti-stress gene response, therapeutic supplements, risk predictor and link to genetic susceptibility. In: 'Oxidative Stress in Applied Basic Research and Clinical Practice: Renal Disorders (Miyata, T., Eckardt, K.-U. and Nangaku, M. eds), Human Press, 93 – 104.

• Thornalley, P.J, Xue, M. and Rabbani, N. (2011) Methodologies for in-vitro and in-vivo activity of bioactive compounds. In: Health-Promoting Properties of Fruits and Vegetables (Terry, L. ed.), CABI, Oxford, UK., in press.

 Other

• Godfrey, L., Thornalley, P.J. and Rabbani, N. (2011) Mimicking the pro-atherogenic phenotype of diabetic dyslipidaemia – glycation by methylglyoxal decreases particle size of HDL2. Diabetic Med., in press. 
• Rabbani, N., Godfrey, L. and Thornalley, P.J. (2011) Atherogenic transformation of LDL by glycation with methylglyoxal – reduction of particle size and increase binding to the aorta in vivo. Diabetic Med., in press.

• Zhang, F., Larkin, J., Godfrey, L., Rabbani, N. and Thornalley, P.J. (2011) Intensive insulin therapy attenuates renal thiamine mishandling in streptozotocin-induced diabetic rats. Diabetic Med., in press.

Publications

2010

• Karachalias, N., Babaei-Jadidi, R., Rabbani, N. and Thornalley, P.J. (2010) Protein glycation, oxidation and nitration in renal glomeruli, retina, nerve, plasma and urine of streptozotocin-induced diabetic rats and effect of thiamine and Benfotiamine therapy. Diabetologia 53, 1506-1516.
• Rabbani, N., Varma Chittari, M., Bodmer C.W., Zehnder, D., Ceriello, A. and Thornalley P.J. (2010) Increased glycation and oxidative damage to apolipoprotein B100 of LDL in patients with type 2 diabetes and effect of thiamine and Benfotiamine therapy. Diabetes 59, 1038-1045.
• Santarius, T., Bignell, G., Greenman, C.D., Widaa, S., Chen, L., Mahoney, C.L., Butler, A., Edkins, S., Waris, S.., Thornalley, P.J., Futreal, A. and Stratton, M.R. (2010) GL01 - a novel amplified gene in human cancer. Chromosome, Genes and Cancer 49, 711-725.
• Thornalley, P.J., Waris, S., Fleming, T., Santarius, T., Larkin, S.J., Winklhofer-Roob, B.M., Stratton, M.R. and Rabbani, N. (2010) Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance. Nucleic Acids Reseasrch, in press.
• Thornalley, P.J., Xue, M. and Rabbani, N. (2010) Methodologies for in-vitro and in-vivo activity of bioactive compounds. In: Health-Promoting Properties of Fruits and Vegetables (Terry, L. ed.), CABI, Oxford, UK., in press.
• Thornalley, P.J., Xue, M. and Rabbani, N. (2010) Thiamine in diabetic and renal disease - dietary insufficiency, renal washout, anti-stress gene response, therapeutic supplements, risk predictor and link to genetic susceptibility. In: 'Oxidative Stress in Applied BGasic Research and Clinical Practice: Renal Disorders', Springer, in press.
• Thornalley, P.J., Xue, M. and Rabbani N. (2010) Oxidation modification of proteins: an overview. In: Biomarkers For Antioxidant Defense And Oxidative Damange Principles And Practical Applications (ldini, G., Yeum, K-J., Niki, E. and Russell, R.M. eds), Wiley-Blackwell, New York, in press.
• Rabbani, N. and Thornalley, P.J. (2010) Dicarbonyls in cola drinks sweetened with sucrose or high fructose corn syrup. The Maillard Reaction: Interface Between Aging, Nutrition and Metabolism (Thomas, M. and Forbes, J. eds), J. Chem. Soc. (London) Special Periodical Report, in press.
• Kurz, A., Rabbani, N., Walter, M., Bonin, M., Thornalley, P.J., Auburger, G. and Gispert, S. (2010) Alpha-synuclein deficiency leads to increased glyoxalase I expression and glycation stress. Cell and Molecular Life Sci., in press.

Chapters in books

• Thornalley, P.J and Rabbani, N. (2010) Oxidation modification of proteins: an overview. In: Biomarkers For Antioxidant Defense And Oxidative Damage Principles And Practical Applications (Aldini, G., Yeum, K.-J., Niki, E., and Russell, R.M. eds.), Wiley-Blackwell, New York, 137 – 156.

• Rabbani, N. and Thornalley, P.J. (2010) Dicarbonyls in cola drinks sweetened with sucrose or high fructose corn syrup. Maillard Reaction: Interface Between Aging, Nutrition and Metabolism (Thomas, M. and Forbes, J. eds.), 158 – 163.

Other

• Karachalias, N., Babaei-Jadidi, R., Rabbani, N. and Thornalley, P.J. (2010) Prevention of decline in glycaemic control in streptozotocin-induced diabetic rats by thiamine but not by Benfotiamine. Diabetic Med. 27, Suppl 1, 74.

Publications

2009

• Foyer, C.H., Faragher, R. and Thornalley, P.J. (2009) Redox metabolism and longevity relationships in animals and plants. Preface: In: Redox Metabolism and Longevity Relationships in Animals and Plants (Foyer,C., Faraghar, R. and Thornalley, P.J. eds), Garland Science, London, xix-xxx, 2009.
• Rabbani.N, Alam, S.S., Riaz. S., Larkin, J.R. Akhtar, N.W., Shafi, T. and Thornalley, P.J. (2009) Thiamine in diabetic nephropathy: a novel treatment modality? Reply to Alkhalaf A., Kleenfsrta N., Groenier KH et al [letter] Diabetologia (2009) 52: 1214-1216
• Vanhorebeek, I., Ellger, B., De Vos, R., Debaveye, Y., Vander Perre, S., Rabbani N., Thornalley P.J., and Van den Berghe, G. (2009) Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness. Critical Care Medicine 37, 1355-1364
• Xue, M.Z., AntonySunil, A., Rabbani, N., and Thornalley, P.J. (2009) Chapter 15. Protein damage by glycation, oxidation and nitration in the ageing process. Advances in quantitation of protein damage and the emerging importance of decline in enzymatic defences as the ageing phenotype develops. In: Redox Metabolism and Longevity Relationships in Animals and Plants (foyer, C., Faraghar, R and Thornalley, P.J. eds). Garland Science, London pp. 227-265
• Thornalley, P.J., and Rabbani N,. (2009) Thiamine and bentotiamine therapy for the prevention of diabetic nephropathy. In: Complications of diabetes mellitus: pathophysiology and pathogenically-based treatment options (Thornalley, P.J. and Kempler, P. eds). Thieme, Stuttgart, Germany, pp 9-17
• Rabbani, N. and Thornalley, P.J. (2009) Thiamine deficiency and renal function in diabetes. In: Complications of diabetes mellitus: pathophysiology and pathogenically-based treatment options (Thornalley, P.J. and Kempler, P eds). Thieme, Stuttgart, Germany, pp 18-25
• VanHolder, R., Abou-Deif, O., Argiles, A., Baurmeister, U., Beige, J., Brouckaert, P., Brunet, P., Cohen G., De Deyn, P.P., Drueke, T.B. Fliser, D., Glorieux, G., Herget-Rosenthal, S., Horl, W.H. Jankowski, J., Jorres, A., Massy, Z.A., Mischak, H., Perna, A.F., Rodriguez-Portill0, J.M., Spasovski, G., Stegmayr, B.G. Stenvinkel, P., Thornalley, P.J. Wanner, C., Wiecek, A. (2009) The Role of EUTox in Uremic Toxin Research. Semin Dial 22, 323-328
• Vanhorebeek, I., Ellger, B., De Vos, R., Debaveye, T., Vander Perre, S., Rabbani, N., Thornalley, P.J. and Van de Berghe, G. (2009) Hypereglycamic damage to renal tissue in an animal model of prolonged critical illness. Kidney Internat. 76, 512-520.
• Bechtold, U., Rabbani, N., Mullineux, P. and Thornalley, P.J. (2009) Quantitative measurement of specific biomarkers for protein oxidation, nitration and glycation in Arabidopsis leaves. Plant Journal 59, 661-671
• Duran-Jimenez, B., Dobler, D., Moffatt, S., Rabbani, N., Streuli, C.h., Thornalley, P.J. Tomlinson, D.R. and Gardiner, N.J. (2009) Advanced Glycation Endproducts in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes. Diabetes 58, 2893-2903
• Rabbani N., Thornalley P J (2009) Quantitation of markers of protein damage by glycation, oxidation, and nitration in peritoneal dialysis. Peritoneal Dialysis International; 29: pp S51-S56
• Rabbani N., Shahzad Alam., Riaz S., Larkin J R., Akhtar M W., Shafi T and Thornalley P J (2009) High dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a pilot randomised, double-blind, placebo-controlled study. Diabetologia 52, pp 208-212
• Wendler A., Irsch T., Rabbani N., Thornalley P J ., Krauth-Siegel R L., (2009) Glyoxalase II does not supprot methylglyoxal deteoxification but serves as a general trypanothione thioesterase in African trypanosomes. Molecular and Biochemical Parasitology 163: pp 19-27
• Schlotterer, A., Kukudov, G., Bozorgmehr, F., Hutter, H., Du, X., Oikonomou, D., Ibrahim, Y., Pfisterer, F., Aydin, D., Rabbani, N., Thornalley, P.J. Sayed, A.A.R., Fleming, T., Humpert, P., Schwnger, V., Zeier, M., Hamann, A., Stern, D., Brownlee, M., Bierhaus, A., Nawroth, P., and Morcos, M. (2009) C. elgans as model for the study of high glucose mediated lifespan reduction. Diabetes 58, 2450-2456.
• Klooster A., Larker J R., Antonysunil A., Gans R O B., Van Good H., Thornalley P J., Rabbani N., Navis G., Leuicenink H G D., Bakker, S J L (2009) Severe thiamine deficiency complicated by weight loss protects against renal ischaemia-reperfusion injury in rats. Nephrology Dialysis Transplant. Plus 2, 182-183
• Thornalley P J., and Rabbani N (2009) Highlights and hotspots of protein glycation in end stages reneal disease. Seminars in Dialysis, 22, 400-404.

Research Interests

Technical Experience

Full List Publications

Research Expertise

Dr Naila Rabbani