Major Research Areas
- Chemokines and their Receptors in T Lymphocyte Activation and Trafficking
This project is part of an extensive ongoing research program aimed at improving our understanding of the role of chemokine receptors in leukocyte activation and migration. The research involves using a number 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 specific chemokine receptors in animal models of inflammatory and chronic diseases including autoimmune disease such a multiple sclerosis, and cancer. This research is not only increasing our understanding of the immune system, it is also allowing us to determine whether targeting chemokine receptors may be useful in treatment of the human equivalent of these diseases. Projects in this area use state-of-the-art techniques, including cell surface and intracellular flow cytometry and cell sorting, RNA sequencing, lentiviral-mediated RNA knock down, generation of novel transgenic and knockout mice, complex animal models of the immune system and human disease.
- 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.
- Genetically Modifying Human Adult Stem Cells to Treat Neuroinflammation
Multiple Sclerosis (MS) is a devastating autoimmune disease of the central nervous system (CNS). Clinically, MS presents in a number of different forms, ranging from mild to severe, and can be relapsing or progressive in nature. In spite of a great deal of research, current therapies are limited. Immunomodulatory drugs can ameliorate MS relapses, but there are currently no therapies capable of inhibiting the progressive form of the disease and development of effective strategies that enhance CNS repair and regeneration is a major research focus. In this regard there has been much recent interest surrounding the use of adult human stem cells in MS. However, while these cells appear to have immunomodulatory, neuroprotective and reparative effects that should be beneficial, a major challenge to their therapeutic use in MS is the difficulty in targeting them into the CNS, and specifically, to sites of tissue damage in MS. there has been much recent interest surrounding the use of adult human stem cells in MS. Over the last decade, we have identified a number of chemokine receptor used by autoreactive T lymphocytes to enter the CNS. In this project, we will test whether forced expression of these receptors on stem cells improves their capacity to migrate specifically and efficiently to the sites of tissue damage in MS, and to test whether this potentiates current stem cell-based therapies in experimental models of MS and leads to CNS regeneration.
- 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. Leukocyte migration and activation in response to chemokines is controlled by a novel intracellular lipid kinase, the p110γ phosphatidylinositol 3-kinase (PI3Kγ). The p110 catalytic subunit of PI3Kγ interacts with at least two novel adaptor proteins, called p101 and p84 and their binding may alter the enzyme’s activity and/or localisation. We have recently shown that PI3Kγ regulates the differentiation of T helper cell subsets in a mouse model of multiple sclerosis and that p84 is a novel extrinsic tumour suppressor in a model of breast cancer. To pursue these discoveries, we have generated a p84 knockout mice, the first in the world. Projects in this area will utilise this mouse to determine the biological role of p84 and its role in animal models of human disease, combining a range of state-of-the-art molecular and cell biological techniques.
- 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.