Graham, Gerard

Chemokines, Stem Cells and Cancer
We have had a long-standing standing interest in chemokines and their receptors and have been working in this field for 18 years. Currently, we have a number of projects that relate to various aspects of chemokine and chemokine receptor function:Studies into the biological function of the D6-chemokine decoy receptor

In 1997 we reported the cloning of the D6 chemokine receptor. D6 is an atypical receptor and can bind many chemokines with high affinity. Interestingly it does not signal following ligand binding and is thus not a typical chemokine receptor. The chemokines that D6 binds are those that are involved in inflammatory responses. D6 internalises ligand and targets it for intracellular degradation. We have thus proposed a role for D6 as a ‘decoy’ or ‘scavenging’ receptor which is capable of internalising and degrading a range of inflammatory chemokines. We have generated D6-nul mice in collaboration with Dr. Don Cook and Prof Sergio Lira and have shown that these mice display an altered ability to resolve inflammation in both the lung and skin. In the skin, following application of a chemical irritant, these D6-null mice develop a pathology which is similar to human psoriasis. Overall our conclusion is that D6 is an indispensable regulator of the in vivo inflammatory response. We are now undertaking a more detailed investigation of the inflammatory response of the D6 null mice using a range of models. We are also generating D6-GFP reporter mice to help us to detail the key cells that express D6 in the inflamed context and the dynamics of expression of D6 during an inflammatory response.

Studies into the structure of D6
D6, although atypical in the biological sense, is a typical seven transmembrane spanning receptor. There is much interest from the pharmaceutical industry in trying to determine the structure of chemokine receptors to aid rational drug design. Currently the only seven transmembrane spanning receptor structure known is that of Rhodopsin. D6 is curious in that it expresses to extremely high levels in heterologous transfectants and we can purify it to homogeneity in a functional form from transfected mammalian cells. We therefore have a very active interest (in collaboration with Prof Neil Isaacs) in determining the full three dimensional structure of the D6 receptor. It is likely that this structure will provide invaluable information on the structures of the other chemokine receptors and will provide a major boost to attempts to rationally design anti-chemokine receptor drugs.
Therapeutic interference with chemokine receptors

We have developing a number of experimental approaches aimed at examining the ability of chemokine receptors to be used as therapeutic targets. For example we have been ‘shrouding’ adenoviruses with chemokines and have been able to use these altered viruses to specifically infect chemokine receptor expressing cells. Such chemokine-virus conjugates will be of use in introducing a range of gene therapy vectors and even cytotoxic vectors to cells of pathological importance. We are also developing a programme of work in collaboration with ALMAC Sciences which is aimed at producing chemokine variants that will be of therapeutic use in a range of pathologies.
Chemokines and stem cells

We are interested in determining the roles for CXC chemokines in haemopoietic stem cell mobilisation and in the recruitment of neutrophils and neutrophil-derived proteases to the stem cell niche. Embryonic Stem Cell studies: We have a range of interests in murine embryonic stem cells from their use as gene targeting vehicles to the control of the induction of haemopoietic differentiation of ES cells in vitro. We are always keen to talk to researchers interested in working in the above areas or in joining our laboratory to work on related projects.

Key publications related to Mye-EUNITER:

  1. C.S. McKimmie, M. Moore, A. Fraser, T. Jamieson, D. Xu, C. Burt, N.I. Pitman, R.J. Nibbs, I.B. McInnes, F.Y. Liew and G.J. Graham (2009) A TLR2 ligand suppresses inflammation by modulation of chemokine receptors and redirection of leukocyte migration. Blood, 113:4224-4231. IF=9.898

  2. K.M. Lee, C.S. McKimmie, D.S. Gilchrist, K.J. Pallas, R.J. Nibbs, P. Garside, V. McDonald, C. Jenkins, R. Ransohoff, L. Liu, S. Milling, V. Cerovic, G.J. Graham (2011). D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion. Blood 118:6220-6229. IF=9.898

  3. M.D. Singh, V. King, H. Baldwin, D. Burden, A. Thorrat, S. Holmes, I.B. McInnes, R. Nicoll, K. Shams, K. Pallas, T. Jamieson, K.M. Lee, J.M. Carballido, A. Rot, G.J. Graham (2012). Elevated Expression of the Chemokine-Scavenging Receptor D6 Is Associated with Impaired Lesion Development in Psoriasis. The American Journal of Pathology. IF=5.571