Chemokines and their receptors in T lymphocyte activation and trafficking

This project area involves investigating the role 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 differentiation, activation and migration using a range of novel reagents including chemokine receptor antagonists, receptor-neutralising antibodies and retroviral/lentiviral knock-down technology and gene knockout mice.

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 cell migration in the context of leukocyte trafficking and cancer metastasis, which will be of benefit in the control of protective and auto immunity and cancer. A lipid kinase, known as the phosphatidylinositol 3-kinase (PI3Kγ), has been implicated in cell signaling in response to ligation of G protein-coupled chemokine receptors by their chemokine ligands. 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 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 p84 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 immunoprecipitation, Western blot, site-directed mutagenesis, lentivirus-mediated RNAi, cell transfection, and proteomics.