Research in the Chemokine Biology Laboratory
The movement of cells is involved in all aspects of life including development, growth and maintenance of organisms.
In spite of this, our understanding of the mechanism involved in cell migration is limited. There are a number of conditions in which the ability to control cell movement would be of significant benefit. Examples include autoimmune conditions, asthma and cancer, the social and economic burdens of which account for billions of dollars and millions of Australians. Research in the Chemokine Biology Laboratory aims to understand the mechanisms that control cell migration. This should produce significant economic and social outcomes in the areas of basic science knowledge, human health, and biotechnology.
Following is a brief description of Honours projects available in the Chemokine Biology Laboratory
Chemokines and their receptors in lymphocyte activation and trafficking
This project area is part of an extensive ongoing research program aimed at improving our understanding of the role of chemokine receptors in leukocyte activation and migration and their relevance to the immune response. This research involves using a range of novel reagents including chemokine receptor antagonists, receptor-neutralising antibodies, 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 the immune response and human diseases including autoimmune disease such a multiple sclerosis, and cancer. The research will identify chemokine receptors that may be useful targets for treatment of the human equivalent of these diseases. State-of-the-art technologies to be used include multiparameter flow cytometry and cell sorting, RNAi, RNA sequencing, proteomics, gene editing and complex models of 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. Recent work has indicated the involvement of a novel intracellular lipid kinase, the phosphatidylinositol 3-kinase (PI3K), in leukocyte activation by chemokines. The p110 catalytic subunit of PI3Kg interacts with at least two adaptor proteins, called p101 and p84 and their binding regulates the enzyme’s activity and/or localisation. Studies in this laboratory have recently shown the importance of this enzyme complex in T cell differentiation. We have also shown that the p84 subunit is a novel extrinsic tumour suppressor. To further investigate these potentially important discoveries, we have made a p84 knockout mouse. Projects in this area involve examining using this novel genetically-modified mouse to investigate these observations. This project will involve a range of in vitro and in vivo experiments, combining a range of cellular and molecular biological techniques with complex models of human disease.