PhD or Honours project opportunities
The following information indicates some of the available research projects. The list is not complete, and interested candidates are encouraged to contact Professor Stocker or members of his staff to discuss the possibility of an alternative research project.
- Control of cellular iron homeostasis by heme oxygenase-1 and its impact on cellular function
- The role of heme oxygenase-1 in vascular tissue repair
- Imaging redox regulation of cellular signaling systems
- Cellular responses to adversity: oxidative stress and protection against oxidative damage in yeast
- The effect of antioxidant drugs on diabetes and insulin resistance and the role of heme-oxygenase-1
- The role of superoxide in the activation of indoleamine 2,3-dioxygenase
- Signalling pathways induced by heme oxygenase-1 in endothelial cells
- Contribution of indoleamine 2,3-dioxygenase to the regulation of vascular tone
Supervisor - Professor Roland Stocker
Project Description - Expression of heme oxygenase-1 profoundly impacts on the cellular iron homeostasis. We observed recently that these changes include alterations in the availability of different cellular iron pools for important biological iron complexes, including iron-sulfur clusters and de novo synthesis of heme. The impact of this on cellular functions, such as mitochondrial respiration, energy metabolism and cell growth are profound. This project will investigate some of the underlying mechanisms, as well as the functional consequences of the altered cellular iron homeostasis in the context of vascular disease and diabetes. The project will use cellular, molecular and biochemical techniques and methodologies.
Supervisor - Professors Roland Stocker
Collaborators - Professors Barry Halliwell and Frank Watt (both National University of Singapore), and Jennifer Gamble (Centenary Institute, Sydney)
Project Description - Injury to a blood vessel results in the induction of heme oxygenase-1 (HO-1) in the underlying layer of smooth muscle cells. We have shown recently that such induction of HO-1 contributes to the eventual repair of the injured blood vessel. We also observed that bone marrow-derived endothelial progenitor cells contribute to the repair process, and that HO-1 also modulates the mobilization and maturation of endothelial progenitor cells from the bone marrow. This project will investigate how iron released as a result of heme oxygenase-1 activity regulates the repair process by progenitor cells. The mechanisms by which changes to circulating iron and or HO-1 activity signal the release of endothelial progenitor cells from the bone marrow will be studied. The project will use a combination of animal studies, and cellular, molecular and physical techniques to address the underlying questions.
Supervisors - Dr Sabine Wimmer-Kleikamp, Dr Ghassan Maghzal, and Professor Roland Stocker
Project Description - This project will develop advanced imaging assays to study temporal and spatial dynamics of redox processes in live cells.
Receptor tyrosine kinases regulate key cellular processes like cell migration, differentiation and proliferation. Abnormal signaling of many family members of kinases has been linked to diseases, such as cancer and vascular disease. Growth factor binding induces receptor oligomerization at the plasma membrane, leading to the activation of receptor tyrosine kinases, and auto trans-phosphorylation of intracellular tyrosine residues. Protein-tyrosine phosphatases regulate receptor tyrosine kinase signaling: they suppress the basal activity of receptor tyrosine kinases and modulate ligand-stimulated signaling. This interplay between activation of receptor tyrosine kinases and inhibition of protein tyrosine phosphatases is regulated tightly by redox-dependent posttranslational protein modifications. However, for many signaling systems, the molecular mechanism underlying such regulation remains elusive.
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 project will provide a better understanding of these complex processes that may allow the development of novel therapies to target abnormal redox-modulated pathways in disease.
4. Cellular responses to adversity: oxidative stress and protection against oxidative damage in yeast
Supervisors - Dr Emma Collinson and Professor Roland Stocker
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.
5. The effect of antioxidant drugs on diabetes and insulin resistance and the role of heme-oxygenase-1
Supervisors - Dr Neil Hime and Professor Roland Stocker
Project Description - Diabetes is characterized by an inability of the body to regulate glucose metabolism. This can be the result of poor secretion of insulin from endocrine cells in the pancreas and/or the inability of tissues to utilize insulin and take up glucose from the blood (insulin resistance). Type 1 diabetes is associated with the former whereas type 2 diabetes is associated with insulin resistance that if left unchecked results in decreased pancreatic insulin secretion.
Probucol is an old antioxidant drug that lowers blood cholesterol and has been used as an anti-atherosclerotic agent but is no longer used clinically in Australia. Probucol has been shown to improve the ability of the pancreas to secret insulin. A derivative of probucol, AGI-1067, has been shown in a large human clinical trial to delay the onset of type 2 diabetes. We are examining the ability of these drugs, and other related compounds, to inhibit type 1 and type 2 diabetes in animal models of these diseases. Our laboratory has previously shown that the anti-oxidant enzyme, heme-oxygenase 1 (HO-1), is the molecular target for probucols’ anti-atherosclerotic effects (J Exp Med 2006;203:1117-1127). We are endeavouring to determine whether the anti-diabetic actions of probucol and related compounds are also mediated via induction of HO-1.
These studies will identify which anti-oxidant compound(s) is favourable to test in clinical trials as diabetic therapy.
Supervisors - Dr Ghassan Maghzal and Professor Roland Stocker
Project Description - Indoleamine 2,3-dioxygenase (IDO) is a cellular heme enzyme that catalyzes the oxidative metabolism of L Tryptophan to kynurenine. The induction of IDO and the formation of kynurenine and its 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 superoxide anion radical (O2-•) is responsible for this reduction. 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-• plays only a minor role. Instead, we have obtained evidence for a role of cytochrome b5 and NAPDH cytochrome P450 reductase in the reductive activation of cellular IDO. This project will examine the role of O2-• versus cytochrome b5 in the activation of IDO in human brain microvascular endothelial cells versus macrophages using a combination of molecular and biochemical approaches.
Supervisors - Dr Robyn Midwinter and Professor Roland Stocker
Project Description - The induction of HO-1 has a number of protective activities in diseases associated with increased oxidative stress, such as cardiovascular, diabetes and inflammatory conditions. It was recently shown that anti-oxidant protection against atherosclerotic disease was closely linked to the induction of HO-1. There is mounting evidence that the up-regulation of HO-1 protects against vascular disease. In addition to promoting re-endothelialization, induction of HO-1 is though to protect via anti-inflammatory activities, inhibition of smooth muscle cell proliferation, and the promotion of endothelial growth. The signalling pathways involved in these protective mechanisms are not well understood. This project will investigate the signalling cascades induced by HO-1 induction and how they alter endothelial proliferation. It will also examine the role of the HO-1 derived compounds CO and Fe on downstream signalling events in endothelial cells. This project will use standard cell culture techniques, molecular biology, Western blotting along with biochemical assays.
Supervisors - Dr Yutang Wang, Professor David Celermajer, Professor Roland Stocker
Collaborators - Associate Professor Annemarie Hennessy and Dr Robert Ogle
Project Description - We have shown recently that in situation of systemic experimental inflammation, endothelial cells express the enzyme indoleamine 2,3-dioxygeanse (IDO) that converts tryptophan to kynurenine. Kynurenine itself relaxes smooth muscle cells via activation of soluble guanylate cyclase, and this can result in a decrease in blood pressure. This project investigates the role of IDO in the regulation of vascular tone in human placenta, and its potential relevance to intrauterine growth. The project requires close interaction with staff at the Royal Prince Alfred Hospital, from where placental material will be obtained. The work will involve vessel function studies, in combination with cellular/mechanistic studies and the integration of the experimental work with clinical outcomes. The project is suited for a scientist or a clinician.
