研究领域

Cardiology (incl. Cardiovascular Diseases)

1. Identification of the redox reactions and cell signaling pathways important for endothelial dysfunction during vascular disease The endothelium is critical for the maintenance of vascular homeostasis. Central to this is endothelium-derived nitric oxide (EDNO), synthesized by the endothelial nitric oxide synthase (eNOS). Vascular diseases including diabetes, atherosclerosis and hypertension are characterized by endothelial dysfunction that is manifested as impaired EDNO bioactivity that contributes to clinical cardiovascular events. Considerable evidence shows that endothelial dysfunction is due to oxidative stress in the blood vessel wall and there is great interest in defining the oxidative processes and cell signalling events involved. Oxidative stress and endothelial dysfunction This project aims to define the oxidative reactions promoting endothelial dysfunction during vascular disease. At present we focus on the oxidative enzyme myeloperoxidase (MPO) that during vascular disease accumulates in the sub-endothelium of diseased blood vessels where it is ideally placed to impact on endothelial function. We are currently investigating the oxidative and cell signalling mechanisms by which MPO impacts on EDNO bioactivity and endothelial function in vascular disease and testing novel agents for their ability to selectively remove MPO from the endothelium. These agents may represent potential therapeutics to combat endothelial dysfunction. Redox control of endothelial cell signalling Reduction and oxidation (redox) reactions represent important transducers of vascular cell signalling pathways. This project aims to identify the redox responsive cell signalling pathways in endothelial cells stimulated with agonists (e.g., vascular endothelial growth factor, angiotensin II) and to define the nature and intracellular source of the redox-active signalling species. 2. Roles and Regulation of Indoleamine 2, 3-Dioxygenase Indoleamine 2, 3-dioxygenase (IDO) is an intracellular heme enzyme that catalyses the catabolism of L-tryptophan (L-Trp). IDO represents a central immune regulatory enzyme. Thus, expression of IDO in professional antigen presenting cells or tumor cells and resultant depletion of L-Trp, the least abundant essential amino acid, inhibits T lymphocyte activation to promote immune suppression and tolerance during inflammation, transplantation, auto-immunity and cancer. IDO and Vascular Disease Atherosclerosis is a chronic inflammatory disease of the artery in which T lymphocyte-mediated immune reactions play an important role. We have detected increased IDO expression in atherosclerotic lesions and currently testing if IDO activity expressed in immune cells inhibits atherosclerosis by limiting T cell activation and vascular inflammation. Regulation of IDO activity In light of the important immune regulatory roles of IDO it is important to understand how the enzyme is controlled. Our previous studies were the first to describe post-translational regulation of IDO and this project aims to characterize the post-translational modifications involved and the extent to which they govern the immune regulatory actions of antigen presenting cells and tumour cells. Identification of how IDO is regulated may facilitate the development of novel drug strategies to modulate IDO activity in vivo.

近期论文

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Thomas SR, 2016, 'Haematopoietic-expressed C/EBPβ: A novel transcriptional regulator of hepatic liver metabolism and macrophage foam cells during atherosclerosis?', Atherosclerosis, vol. 250, pp. 183 - 185, http://dx.doi.org/10.1016/j.atherosclerosis.2016.05.015 Thoms JAI; Knezevic K; Liu JJ; Glaros EN; Thai T; Qiao Q; Campbell H; Packham D; Huang Y; Papathanasiou P; Tunningley R; Whittle B; Yeung AWS; Chandrakanthan V; Hesson L; Chen V; Wong JWH; Purton LE; Ward RL; Thomas SR; Pimanda JE, 2016, 'Arrested hematopoiesis and vascular relaxation defects in mice with a mutation in Dhfr', Molecular and Cellular Biology, vol. 36, no. 8, pp. 1222 - 1236, http://dx.doi.org/10.1128/MCB.01035-15 Huang Y; Thoms JAI; Tursky ML; Knezevic K; Beck D; Chandrakanthan V; Suryani S; Olivier J; Boulton A; Glaros EN; Thomas SR; Lock RB; MacKenzie KL; Bushweller JH; Wong JWH; Pimanda JE, 2016, 'MAPK/ERK2 phosphorylates ERG at serine 283 in leukemic cells and promotes stem cell signatures and cell proliferation', Leukemia, vol. 30, no. 7, pp. 1552 - 1561, http://dx.doi.org/10.1038/leu.2016.55 Tran J; Magenau A; Rodriguez M; Rentero C; Royo T; Enrich C; Thomas SR; Grewal T; Gaus K, 2016, 'Activation of endothelial nitric oxide (eNOS) occurs through different membrane domains in endothelial cells', PLoS One, vol. 11, no. 3, http://dx.doi.org/10.1371/journal.pone.0151556 Liou K; Jepson N; Buckley N; Chen V; Thomas S; Russell EA; Ooi SY, 2016, 'Design and Rationale for the Endothelin-1 Receptor Antagonism in the Prevention of Microvascular Injury in Patients with non-ST Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Inter', Cardiovascular Drugs and Therapy, vol. 30, no. 2, pp. 169 - 175, http://dx.doi.org/10.1007/s10557-016-6641-x Yeung AWS; Terentis AC; King NJC; Thomas SR, 2016, 'Role of indoleamine 2,3-dioxygenase in health and disease', Clinical Science, vol. 129, no. 7, pp. 601 - 672, http://dx.doi.org/10.1042/CS20140392 Rees MD; Thomas SR, 2015, 'Using cell-substrate impedance and live cell imaging to measure real-time changes in cellular adhesion and de-adhesion induced by matrix modification', Journal of Visualized Experiments, no. 96, http://dx.doi.org/10.3791/52423 Nasrallah R; Knezevic K; Thai T; Thomas SR; Göttgens B; Lacaud G; Kouskoff V; Pimanda JE, 2015, 'Endoglin potentiates nitric oxide synthesis to enhance definitive hematopoiesis', Biology Open, vol. 4, no. 7, pp. 819 - 829, http://dx.doi.org/10.1242/bio.011494 Das T; Kutty SK; Tavallaie R; Ibugo AI; Panchompoo J; Sehar S; Aldous L; Yeung AWS; Thomas SR; Kumar N; Gooding JJ; Manefield M, 2015, 'Phenazine virulence factor binding to extracellular DNA is important for Pseudomonas aeruginosa biofilm formation', Scientific Reports, vol. 5, http://dx.doi.org/10.1038/srep08398 Di Bartolo BA; Cartland SP; Prado-Lourenco L; Griffith TS; Gentile C; Ravindran J; Azahri NS; Thai T; Yeung AW; Thomas SR; Kavurma MM, 2015, 'Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia-Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide-Dependent Mechanisms.', Journal of the American Heart Association, vol. 4, no. 11, http://dx.doi.org/10.1161/JAHA.115.002527 Rees MD; Thomas SR, 2015, 'Using cell-substrate impedance and live cell imaging to measure real-time changes in cellular adhesion and de-adhesion induced by matrix modification', Journal of Visualized Experiments, no. 96, http://dx.doi.org/10.3791/52423 Maiocchi SL; Thomas SR; Rees MD, 2014, 'Regulation of the NO Oxidase Activity of Myeloperoxidase by Pharmacological Agents', Free Radical Biology and Medicine, vol. 76, pp. S17 - S17, http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.497 Sherrah AG; Edelman JJB; Thomas SR; Brady PW; Wilson MK; Jeremy RW; Bannon PG; Vallely MP, 2014, 'The freestyle aortic bioprosthesis: A systematic review', Heart Lung and Circulation, vol. 23, no. 12, pp. 1110 - 1117, http://dx.doi.org/10.1016/j.hlc.2014.04.262 Cochran BJ; Bisoendial RJ; Hou L; Glaros EN; Rossy J; Thomas SR; Barter PJ; Rye KA, 2014, 'Apolipoprotein A-I increases insulin secretion and production from pancreatic β-cells via a G-protein-cAMPPKA-FoxO1-dependent mechanism', Arteriosclerosis, Thrombosis and Vascular Biology, vol. 34, no. 10, pp. 2261 - 2267, http://dx.doi.org/10.1161/ATVBAHA.114.304131 Rees MD; Maiocchi SL; Kettle AJ; Thomas SR, 2014, 'Mechanism and regulation of peroxidase-catalyzed nitric oxide consumption in physiological fluids: Critical protective actions of ascorbate and thiocyanate', Free Radical Biology and Medicine, vol. 72, pp. 91 - 103, http://dx.doi.org/10.1016/j.freeradbiomed.2014.03.037 Stapelberg M; Zobalova R; Nguyen MN; Walker T; Stantic M; Goodwin J; Pasdar EA; Thai T; Prokopova K; Yan B; Hall S; De Pennington N; Thomas SR; Grant G; Stursa J; Bajzikova M; Meedeniya ACB; Truksa J; Ralph SJ; Ansorge O; Dong LF; Neuzil J, 2014, 'Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans', Free Radical Biology and Medicine, vol. 67, pp. 41 - 50, http://dx.doi.org/10.1016/j.freeradbiomed.2013.10.003 Sherrah AG; Edelman JJB; Thomas SR; Brady PW; Wilson MK; Jeremy RW; Bannon PG; Vallely MP, 2013, 'The Freestyle Aortic Bioprosthesis: A Systematic Review', Heart Lung and Circulation, http://dx.doi.org/10.1016/j.hlc.2014.04.262 Rivera J; Hooker EU; Guida E; Sobey CG; Drummond GR; Walduck AK; Thomas SR; Glaros EN, 2013, 'Accumulation of serum lipids by vascular smooth muscle cells involves a macropinocytosis-like uptake pathway and is associated with the downregulation of the ATP-binding cassette transporter A1', Naunyn-Schmiedebergs Archives of Pharmacology, pp. 1 - 13, http://dx.doi.org/10.1007/s00210-013-0909-5 Freewan M; Rees MD; Sempértegui Plaza TS; Glaros E; Lim YJ; Wang XS; Yeung AWS; Witting PK; Terentis AC; Thomas SR, 2013, 'Human Indoleamine 2,3-dioxygenase is a catalyst of physiological heme peroxidase reactions:implications for the inhibition of dioxygenase activity by hydrogen peroxide', Journal of Biological Chemistry, vol. 288, no. 3, pp. 1548 - 1567, http://dx.doi.org/10.1074/jbc.M112.410993 Yeung AWS; Wu W; Freewan M; Stocker R; King NJC; Thomas SR, 2012, 'Flavivirus infection induces indoleamine 2,3-dioxygenase in human monocyte-derived macrophages via tumor necrosis factor and NF-κB', Journal of Leukocyte Biology, vol. 91, no. 4, pp. 657 - 666, http://dx.doi.org/10.1189/jlb.1011532