Click here for a general introduction to our work. Suitable for the general public.
Click here for more detailed information on our research interests. Suitable for scientists, clinicians and students.
We are interested in a number of research areas and have projects focussing on different aspects of cell migration and nitric oxide signalling. A brief outline of these projects is given below.
Cell migration is an important process in the immune response, placental development, angiogenesis, cancer metastasis and during embryo development. In migrating cells the leading edge of the cell demonstrates membrane protrusion, adhesion site formation and the generation of force. The protrusion of the plasma membrane and the formation of the lamellipodium, is driven by polymerisation of actin at the cell front. We have found that NO plays an important role in regulating this process. Nitric oxide promotes increased cell movement in many cell types and we have shown that isoforms of nitric oxide synthsase re-distribute in the cell duing migration to localise to regions of the cell that are most involved in the cell movement such as the leading edge and the cytoskeleton.
We are interested in the mechanisms of NO stimulated cell motility and seek to identify the molecular targets of NO in actively migrating cells and to determine the functional consequences of NO modification.
We are also particularly interested in a type of cell movement based on membrane blebbing, often termed amoeboid movement. This type of movement can be seen in 3D environments such as cancer cells embedded in Matrigel or collagen gels. When their ability to degrade the extracellular matrix is inhibited these cells can switch to a type of movement involving membrane blebs rather than lamellipodia. We have also observed this type of movement in skeletal muscle stem cells migrating along damaged muscle fibres and seek to understand how the regulation of blebs controls cell migration.
Mathematical modelling of biological processes is becoming increasingly important in an attempt to better understand the underlying principles governing cell behaviour. We are interested in developing, in collaboration with colleagues from the Centre for Mathematical Biology at the University of Oxford, mathematical models to describe cell movement, particularly focussing on bleb based, or amoeboid, motility. Developing rigourous mathematical models of this process will help to identify critical components of the system and make predictions about the likely behaviour of cells under different conditions that will help refine the model and generate a more sophisticated and quantitative understanding of cell motility.
Resistance to therapy is a major issue in cancer treatment. In many cases tumours are initially responsive to treatment with chemotherapy drugs and tumours can shrink leading to patients entering remission. Unfortunately in some cases the tumours can return and when they do they have often developed resistance to the intial treatment and are no longer responsive to chemotherapy. We are interested in the mechanisms that regulate apoptosis resistance in cancer as a possible explanation of some chemotherapy resistance. We are investigating the role of nitric oxide (NO) and other cell signalling pathways in the regulation of apoptosis in cancer and also investigating the tumour environment on their sensitivity to apoptosis.
S-nitrosylation of proteins is a major mechanism through which the effects of nitric oxide (NO) are mediated. It is a physiologically important post-translational modification of cysteine residues that affects a wide variety of proteins involved in a number of cellular processes. Like other post-translational modifications, such as phosphorylation, nitrosylation exhibits substrate specificity, strict spatial and temporal regulation and is reversible.
A wide range of proteins have been identified as being nitrosylated including apoptotic proteins such as the caspases, intracellular signalling proteins such PKC and Src kinase, and proteins involved in cell migration and invasion such as MMP-9 and RhoA. Nitrosylation can both inhibit or stimulate protein activity depending on the protein that is nitrosylated. In many cases the functional consequences of nitrosylation are not known.
We are interested in the regulation of protein nitrosylation, including addressing questions such as the mechanisms for achieving substrate specificity and identifying the functional consequences of nitrosylation.