Major research areas
Chemokines and their receptors in T lymphocyte activation and trafficking
This project area involves using a range of novel reagents including chemokine receptor antagonists, receptor-neutralising antibodies and retroviral/lentiviral knock-down technology and gene knockout mice as tools to probe for the involvement of the specific chemokine receptors in animal models of inflammatory and chronic diseases including autoimmune disease such a multiple sclerosis and cancer. This could, in turn, determine whether such an approach may be useful in treatment of the human equivalent of these diseases, as well as providing important information regarding basic aspects of immune system function. This work is part of an extensive ongoing research program aimed at improving our understanding of the role of chemokine receptors in T cell activation and migration. Projects in this area are aimed at evaluating the ability of novel chemokine antagonists and decoy receptors to attenuate the autoimmune disease experimental autoimmune encephalomyelitis, and to modify tumour growth and metastasis.
Understanding chemokine signalling in cancer
Approximately 90% of all cancer deaths arise from the metastatic spread of primary tumors. Of all the processes involved in carcinogenesis, local invasion and the formation of metastases are clinically the most relevant, but they are the least well understood at the molecular level. Revealing their mechanisms is one of the main challenges for the basic and applied cancer research. Recent experimental progress has implicated chemokines and their receptors in the multistage process of metastasis formation. For instance, the chemokine receptors CXCR4 and CCR7 are frequently expressed on metastatic breast cancer cells, and their ligands, SDF1/CXCL12 and CCL21, respectively, are expressed by lung and regional lymph nodes — frequent sites of breast cancer metastasis. However the identification of the pathways downstream of the chemokine receptors in cancer cells and their functional contributions to the metastatic spread remain to be explored and will constitute the central objective of this project. Our recent novel findings suggest a role for these chemokine receptors as survival factors in metastatic cancer cells. Projects in this area use a combination of cellular assays and animal models to further advance these novel findings via utilizing RNAi, genetic manipulations and proteomics technologies.
Role of the class IB PI 3kinase in cell activation/migration by chemokines
Understanding the intracellular mechanisms regulating cell function in response to chemokines is important since such knowledge is likely to enable us to more specifically control leukocyte trafficking and therefore protective and auto immunity. Recent work has indicated the involvement of a novel intracellular lipid kinase, the p110g phosphatidylinositol 3-kinase (PI3Kγ), in leukocyte activation by chemokines. The p110 catalytic subunit of PI3Kγ interacts with at least two novel adaptor proteins, called p101 and p87 and their binding may alter the enzyme’s activity and/or localisation. We have cloned these components and prepared many unique cutting-edge reagents to allow state-of-the-art experimentation in this area. We have also identified novel components of this signaling complex using proteomics. Projects in this area involve examining the role of the p101 and p87 subunits and these novel subunits in chemokine-mediated cell activation and migration in vitro and in vivo, combining a range of molecular biological techniques including immunprecipitation, Western blot, site-directed mutagenesis, lentivirus-mediated RNAi, cell transfection, and proteomics.
Collaboration with the Adelaide Proteomics Centre (with Dr. Peter Hoffmann).
The Adelaide Proteomics Centre is a new initiative within the School of Molecular & Biomedical Sciences. The Centre has the latest mass spectrometry technology to identify proteins and their posttranslational modifications. The Centre also has the latest technology in differential fluorescence and isotopic labelling of complex protein mixtures including their separation and imaging in order to provide direct measurement of protein expression levels. The Chemokine Biology Laboratory has a close collaboration with Dr Peter Hoffmann, the Director of the Adelaide Proteomics Facility, and many of the projects offered in the Chemokine Biology Laboratory involve proteomics approaches.
Funding Sources
Projects in Chemokine Biology are funded by grants from the National Health & Medical Research Council of Australia, the Australian Research Council, the National Multiple Sclerosis Society USA, Multiple Sclerosis Australia and the Australian Cancer Research Foundation.
