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Research interests

Cytokines are potent mediators of cell-cell communication, whose expression and functions are tightly regulated at the level of magnitude and duration, by transcriptional and post-translational mechanisms.

Upon binding to their cognate receptors, virtually all cytokines signal by activating the evolutionarily conserved JAK-STAT signalling pathway leading to regulation of  diverse cellular functions ranging from embryonic stem cell renewal to regulation of the immune system. There are four Janus activated Kinases (JAK1-3 and Tyk2) and seven signal transducers and activators of transcription proteins (STAT1-4, 5a, 5b and 6).

The biological importance of the JAK-STAT signalling pathway was indicated by the severe combined immunodeficiency (SCID) of patients lacking functional JAK3 kinase, that associates exclusively with the common gamma-chain (γc), which is shared by members of the immunologically important IL-2-family of cytokines. Additionally, genetic mutations in Tyk2, STAT1, STAT3, and STAT5B have been shown to cause various immunodeficiencies, indicating the profound importance of an intact JAK-STAT signaling pathway to normal cellular integrity and immune function.

By virtue of the fact that STAT proteins play vital roles in the proliferative, differentiation and survival decisions of cells, constitutively activated STATs, particularly STAT3 and STAT5, have been detected in a variety of human primary tumours, haematopoietic tumours such as leukaemias, lymphomas, multiple myelomas and cellular transformation by viral or cellular oncogenes. Previously, we showed that dysregulation of STAT5 proteins contributes to the pathology of malignant T cells in Sezary Syndrome. Moreover, over-expression of constitutively activated STAT3 and STAT5, or wild-type or a C-terminally truncated form of Stat5 (Stat5t), induced tumours in transgenic mouse models, suggesting that these two STAT proteins regulate transcription of important target genes, whose aberrant expression can lead to cellular transformation.

We are interested in understanding the molecular mechanisms by which STAT5A, STAT5B and to a lesser extent STAT3, mediate the actions of IL-2 in T cells. As IL-2 regulates many critical aspects of immunity, such as activation induced cell death (AICD) of T cells, tolerance and autoimmunity, via the JAK-STAT5 pathway, a detailed molecular understanding of how these STAT proteins are regulated, and the target genes they regulate should enable us to identify novel therapeutic targets for use in diseases associated with the dysregulation of IL-2/IL-2R system. To this extent we are undertaking structure-function studies of the two highly homologous proteins, STAT5A and STAT5B to understand how they interact with DNA, and whether they differ in this process.  In other studies, we have identified a number of novel IL-2-induced target genes of STAT5A and STAT5B by chromatin immunoprecipitation, and studies are underway to validate and evaluate several of these candidate genes at the expression and functional level.  We also have on-going collaboration with the lab of Prof. Giovanna Lombardi and Prof. Robert Lechler on the role of STAT3/STAT5 in Treg cell differentiation under inflammatory conditions.

Research interests (short)

Understanding the molecular mechanisms of action of cytokines, particularly IL-2, in T and B cells.

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being


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