The work of this group is directed to gaining a better understanding of the pathogenesis of cancer and inflammatory diseases such as atherosclerosis and rheumatoid arthritis. We would then like to utilise this knowledge to improve diagnosis, management and therapy of the conditions in question. We have focussed our studies around 2 proteins, MIC-1 and CLIC1, first identified and characterised in this laboratory in the 1990’s, on the basis of increased expression with macrophage activation. We plan to continue and extend our knowledge with observations into the following areas:
MIC-1
Identify and characterise the MIC-1 receptor and its signalling pathways.
Further elucidate the role of MIC-1 in the biology of cancer.
Elucidate the role of MIC-1 in cancer cachexia, weight and appetite control.
Establish MIC-1 serum level determination and genotyping as a diagnostic test for cancer diagnosis and management and commercialise this technology.
Undertake a therapeutic trial of monoclonal antibody to MIC-1, to determine if it is effective in treatment of cancer cachexia in humans, as it is in the animal model.
Further elucidate the role of MIC-1 in regulating immune and inflammatory responses.
The role of CLIC-1 in regulating platelet function.
The mechanism of action of CLIC1 in the regulation of the immune and inflammatory responses.
In collaboration with the groups of Prof Paul Curmi, and Prof Michele Mazzanti, define the structure/function relationship of CLIC1 and obtain the high resoltution structure of the membrane form of this protein
The role of CLIC-1 in the regulation of immune and inflammatory responses.
An understanding of structure/function is an essential element in understanding molecule function and our group has started to unravel this in the CLIC family. Our collaborators (Prof Paul Curmi’s group) have solved the high-resolution crystallographic structure of the soluble form of CLIC1, the first high-resolution study of a member of this family and more recently the structure of CLIC4, drosophila CLIC and EXC-4. CLIC1 is a structural homolog of the glutathione-S-transferases (GST) and contains a glutathione (GSH) binding site motif but does not bind reduced GSH. CLIC1 must undergo significant conformational change from its globular, soluble structure in order to form an ion channel. Its GST-like structure provides a strong argument for the role of oxidation/reduction/GSH in the function of CLIC1 and pursuing this line of reasoning, we have shown that on oxidation, CLIC1 undergoes a reversible transition from a monomeric to a non-covalent dimeric state, due to the formation of an intra-molecular disulphide bond (Cys24-Cys59). We have determined the crystal structure of this oxidised state, and show that a major structural transition has occurred, exposing a large hydrophobic surface, which forms the dimer interface. The oxidised CLIC1 forms Cl- channels in artificial bilayers and vesicles, while a reducing environment prevents the formation of ion channels. Initial mutational studies suggested that
The work of this group is directed to gaining a better understanding of the pathogenesis of cancer and inflammatory diseases such as atherosclerosis and rheumatoid arthritis. We would then like to utilise this knowledge to improve diagnosis, management and therapy of the conditions in question. We have focussed our studies around 2 proteins, MIC-1 and CLIC1, first identified and characterised in this laboratory in the 1990’s, on the basis of increased expression with macrophage activation. We plan to continue and extend our knowledge with observations into the following areas: