Centre Head
Professor Roland Stocker
Discipline of Pathology
Level 1
Medical Foundation Building (K25)
92-94 Parramatta Road
Camperdown, NSW, 2042
Phone: +61 2 9036 3207
Fax: +61 2 9036 3286
Email: rstocker@med.usyd.edu.au
Centre Personnel
Head |
Research Staff |
Technical Staff Ms Jie Liu |
Personal Assistant Ms Katie Hodgetts |
Research Overview
The research program in our laboratory focuses on oxidative processes in vascular medicine
Current research projects aim to:
Current Research
The role of heme oxygenase as an antioxidant defense
Supervisors: Professors Roland Stocker (Pathology)
and Ian Dawes (UNSW), and Dr Emma Collinson (Pathology)
Contact Details: Level 2, Medical Foundation Building
(K25), Email: rstocker@med.usyd.edu.au,
Phone: 9036 3207
Project
Description: Heme oxygenase catalyzes the oxidative
degradation of heme and plays a key role in iron homeostasis by facilitating
the ‘return’ of heme-derived iron to the bone marrow where
it can be used for hematopoiesis. A large body of recent literature suggests
that one of the isozymes of heme oxygenase (heme oxygenase-1) has a number
of protective activities in diseases associated with increased oxidative
stress, such as cardiovascular, neurodegenerative and inflammatory conditions.
The mechanisms underlying these protective effects are largely unknown,
although antioxidant protection has been put forward as one likely possibility.
Recently, a functionally active yeast heme
oxygenase has been identified. The role of HMX1 in controlling intracellular
heme levels has been elucidated. However, little is known about whether
it offers protection against oxidative stress and whether its expression
is redox regulated. This project will use standard yeast molecular techniques
and biochemistry to address these questions.
Control of growth of vascular cells by heme oxygenase-1
Supervisors: Dr Konstanze Beck and Professor Roland
Stocker (Pathology)
Contact Details: Level 2, Medical Foundation Building
(K25), Email: kbeck@med.usyd.edu.au,
Phone: 9036 3212
Project
Description: Atherosclerosis is the major single
cause of cardiovascular disease (CVD) that itself remains the single major
cause of death in Western countries including Australia. While lipid-lowering
drugs (e.g., statins) have been extremely successful in lowering CVD,
there nevertheless is an urgent need for the development of novel drugs
that protect against atherosclerotic vascular disease by means other than
lipid lowering. We recently identified heme oxygenase 1 (HO 1) as a target
of the anti-atherosclerotic action of an old, now uncommonly used, drug
(probucol) and are developing novel probucol analogs that share the beneficial
but not undesirable side effects of probucol. Regulation of HO 1 by probucol
and the novel drugs we are developing provides several protective effects
in vivo, including the promotion of re-endothelialization and the inhibition
of excessive proliferation of vascular smooth muscle cells. In vitro studies
confirm that the novel drugs induce HO 1 mRNA, protein and activity in
vascular smooth muscle cells, and this is directly responsible for the
inhibition of excessive growth of these cells. However, at present, we
know much less about how the novel drugs exert this striking cell-specific
effect, i.e., they promote (rather than inhibit) the growth of endothelial
cells. As hydrogen peroxide (H2O2) is the only agent known to have such
cell type-specific effect, this project will investigate the effect of
the novel drugs on enzymes involved in H2O2 synthesis and metabolism.
This will be examined in both endothelial and vascular smooth muscle cells.
The techniques involved include cell culture, molecular techniques (e.g.,
to increase and decrease HO 1 expression) and biochemical methods (to
relate differences in HO 1 activity to differences in peroxidase activity).
The role of heme oxygenase-1 in cerebral malaria infection
Supervisors: Professor Roland Stocker (Pathology)
and Professor Nick Hunt (Pathology)
Contact Details: Level 2, Medical Foundation Building
(K25), Email: rstocker@med.usyd.edu.au,
Phone: 9036 3207
Project
Description: High activity of heme oxygenase 1 (HO
1) in host brain and in tissue macrophages has recently been reported
to protect against experimental cerebral malaria, and this protective
effect could be recapitulated by administration of carbon monoxide (CO),
a metabolic product of heme oxygenase activity. It is thought that CO
binds to hemoglobin released from erythrocytes undergoing rupture during
the blood stage of the parasite life cycle, and by doing so prevents hemoglobin
from releasing the toxic heme that otherwise damages endothelial cells
and contributes to the adherence to, and hence accumulation of, CD8+ T
cells in cerebral blood vessels. The latter event has been intimately
linked to the pathogenesis of cerebral malaria. High endogenous activity
of heme oxygenase, or induction of HO-1 by pharmaceutical agents, is thought
to protect against cerebral malaria because it results in enhanced generation
of CO.
As heme plays a central role in the proposed
new function of HO-1, this project will examine (i) the potential role
of the heme-binding protein hemopexin in cerebral malaria, (ii) where
precisely HO-1 is induced during infection, and (iii) whether metabolic
products in addition to CO may impact on disease outcome. For this, the
mouse model of cerebral malaria established in the laboratory of Professor
Hunt will be used in conjunction with techniques available in the laboratory
of Professor Stocker. The outcome of malarial infection will be assessed
by survival, neurological and biochemical parameters.
Imaging redox regulation of cellular signalling systems
Supervisors: Dr Sabine Wimmer-Kleikamp and Professor Roland Stocker (Pathology)
Contact Details: Level 2, Medical Foundation Building
(K25), Email: swimmer@med.usyd.edu.au,
Phone: 9036 3212
Project
Description: If you chose this project you will become familiar with a number of cutting edge microscopy and imaging technologies, in combination with biochemical and molecular biology methods. Receptor tyrosine kinases (RTKs) regulate key cellular processes like cell migration, -differentiation and -proliferation. Abnormal signalling of many family members has been linked to diseases, such as cancer and vascular disease. The aim of this project is to identify oxidants and enzymes that affect the redox state and redox processes following receptor tyrosine kinase activation on endothelial cells. We will approach this question from both a cellular biology and biochemical perspective and test the functional relevance of our findings in experimental animal models. This multifaceted project will provide a better understanding of these complex processs, which may allow the development of novel therapies to target abnormal redox-modulated pathways in endothelial disease.
Role of cytochrome b5 in the reductive activation of indoleamine 2,3-dioxygenase
Supervisors: Dr Gus Maghzal and Professor Roland Stocker (Pathology)
Contact Details: Level 2, Medical Foundation Building
(K25), Email: rstocker@med.usyd.edu.au,
Phone: 9036 3207
Project
Description: Human indoleamine 2,3-dioxygenase (IDO) is an intracellular heme enzyme that catalyzes the oxidative metabolism of L-Tryptophan (L-Trp) along the kynurenine (kyn) pathway. The induction of IDO and the formation of kynurenine pathway metabolites have been implicated in processes such as immune regulation, neuropathology, microbial and tumor defense and more recently by our group in the regulation of vascular tone.
IDO requires to be activated via reduction of its ferric heme. For the last 30 years, the dogma has been that IDO requires and consumes superoxide anion radical (O2-.) to metabolise L-Tryp to Kyn. We observed that O2-. can also activate recombinant human IDO. However, the extent of this activation is modest, and small changes in the cellular concentration of O2-. barely affect IDO activity, suggesting that O2-. play s only a minor role. Instead, we have recently obtained evidence for a role of microsomal cytochrome b5 and NAPDH cytochrome P450 reductase in the activation of cellular IDO. In this project, we will investigate the mechanisms of cytochrome b5-induced activation of IDO by examining whether a physical interaction is required. We will also investigated if the mitochondrial form of cytochrome b5 is also involved in the activation of IDO.
Latest Publications
Grants Awarded