Our research in detail

Understanding how redox processes contribute to atherosclerosis, related disorders and diabetes; and how this can be exploited to develop novel therapeutics

• Recent milestones and important events
• Background
• Current work
• Research approach and equipment
• PhD or Honours project opportunities
• Current collaborators

1. Licensed IP related to novel molecules as anti-atherosclerotic agents to pharmaceutical company in the United States.
2. Identified cytochrome b5 as a cellular reductant for the enzyme indoleamine 2,3-dioxygenase.
3. Dr Sabine Wimmer-Kleikamp, a CJ Martin Fellow, joined the group in February 2008.

The "Oxidative Modification Theory of Atherosclerosis" predicts that oxidative modification of low-density lipoprotein (LDL) is an early event in and a cause of atherogenesis. Indeed, heightened oxidative stress and oxidative modifications to LDL are key features of atherosclerosis and related diseases. However, atherosclerosis-associated oxidative modifications are not specific for, or limited to, LDL. Also, large prospective studies testing the protective role of natural antioxidants such as vitamin E on cardiovascular disease outcome have yielded disappointing results. This questions the relationship of LDL oxidation and atherosclerosis, as well as the role antioxidants may play in these processes. Past work of our group has helped explain why vitamin E fails to provide protection against atherosclerosis. We have also shown that, in contrast to vitamin E, the synthetic antioxidant probucol consistently prevents atherosclerotic vascular diseases in animals. This protection does not depend on inhibition of LDL oxidation in diseased vessels, but instead requires the drug to induce the protein heme oxygenase-1 (HO-1). We have identified the chemical parts of probucol required for its in vivo efficacy and, in conjunction with industry, are aiming at developing some of our patented novel compounds as anti-atherosclerotic drugs.

1. A major focus of our work is increasing existing knowledge on HO-1 biology, at the cellular, tissue, and whole body level. The aim is to better understand how induction of the enzyme results in so many different biological benefits, including anti-inflammatory activity, increased protection provided to the endothelium against injury and dysfunction, and the control of cell growth. An immerging interest of our group is the role of HO 1 in diabetes.
2. We continue studying the regulation and biological function of the enzyme indoleamine 2,3-dioxygenase (IDO), with a particular focus on its role in the vasculature under conditions of inflammation and oxidative stress, including cardiovascular diseases.
3. We are assessing the utility of a recently generated monoclonal antibody that recognizes oxidized high-density lipoprotein as a diagnostic for cardiovascular disease.
4. We are developing analytical tools to assess the occurrence of oxidative processes in different cellular compartments and quantify their contribution to cellular functions.

Our research approach is multidisciplinary, ranging from chemical synthesis to human applications, the latter through our links with the Department of Cardiology at the Royal Prince Alfred Hospital. We utilize purified enzymes, yeast genetics, mammalian cell culture, blood vessels and other tissue, histology, various animal models of atherosclerotic vascular disease and diabetes, and human tissue. The technologies employed include analytical tools (in biochemistry, chemistry and physics), cell and molecular biological tools, functional studies related to blood vessels, histology and immunohistochemistry, microscopy and state-of-the art imaging, as well as morphometry and whole body metabolic tests.

For more details, see PhD or Honours project opportunities

1. Control of cellular iron homeostasis by heme oxygenase-1 and its impact on cellular function
2. The role of heme oxygenase-1 in vascular tissue repair
3. Imaging redox regulation of cellular signaling systems
4. Cellular responses to adversity: oxidative stress and protection against oxidative damage in yeast
5. The effect of antioxidant drugs on diabetes and insulin resistance and the role of heme-oxygenase-1
6. The role of superoxide in the activation of indoleamine 2,3-dioxygenase
7. Signalling pathways induced by heme oxygenase-1 in endothelial cells
8. Contribution of indoleamine 2,3-dioxygenase to the regulation of vascular tone
9. Novel markers of oxidative stress and their utility in the diagnosis of cardiovascular disease

• Professor David Celermajer (Royal Prince Alfred Hospital)
• Professor Kevin Croft (University of Western Australia)
• Professor Jennifer Gamble (Centenary Institute, Sydney)
• Professor Barry Halliwell (National Uniaversity of Singapore)
• Professor Jay Heineicke (University of Washington, Seattle)
• Associate Professor Annemarie Hennessy (University of Western Sydney, Sydney)
• Professor Nicholas Hunt (University of Sydney)
• Professor David James (Garvan Institute, Sydney)
• Dr Martin Lackmann (Monash University, Melbourne)
• Dr Antony Lau (Eastern Heart Clinic, Sydney)
• Professor Peter Lay (University of Sydney, Sydney)
• Professor Levon Khachigian (University of New South Wales)
• Dr Robert Ogle (Royal Prince Alfred Hospital, Sydney)
• Professor Des Richardson (University of Sydney, Sydney)
• Associate Professor Chris Sobey (Monash University, Melbourne)
• Dr Hans-Peter Stasch (Institute of Cardiovascular Research, Bayer HealthCare, Wuppertal)
• Dr Shane Thomas (University of New South Wales)
• Professor Leanne Tilley (La Trobe University)
• Professor Frank Watt (National University of Singapore)
• Professor Markus Wenk (National University of Singapore)
• Dr Paul Witting (University of Sydney)