The Redox Cell Signalling Laboratory focuses on two major research areas:
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.
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.
Broad Research Areas:
Cardiology and Vascular Disease, Immunology, Cell Biology and Gene Regulation, Biochemistry, Cancer
Society Memberships & Professional Activities:
Australasian Society for Free Radical Research, Australian Vascular Biology Society, Australian Society for Medical Research
Specific Research Keywords:
Vascular Biology, Cell Biology and Immunology, Cancer, Inflammation, Nitric oxide