Project: The Mechanism by which the Protein Kinase Tpl2 is Activated by IL-1
Place: College of Life Sciences, Sir James Black Centre, University of Dundee
Supervisor: Prof. Sir Philip Cohen (group page)
Duration:
1 October 2007 – 30 September 2008 (Bachelor graduation research project)
1 October 2008 – 30 September 2011 (Postgraduate project)
Infection by pathogens, such as bacteria, triggers cells of the immune system to produce proinflammatory cytokines, such as tumour necrosis factor (TNF), which are released into the blood to mount responses that combat the invading pathogen. However, this defence mechanism is a double-edged sword because the uncontrolled production of proinflammatory cytokines is a major cause of chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and asthma, as well asseptic shock. Therefore, there is great interest in understanding how pro-inflammatory cytokines are produced so that drugs can be developed to suppress their production and so treat these diseases.
The protein kinase Tpl2 is activated by bacterial infection. It plays a key role in the production of TNF and mice that do not express Tpl2 are protected against inflammatory bowel disease. Tpl2 is therefore a potential target for the development of anti-inflammatory drugs and understanding how it is activated is of great interest. The Tpl2 complex comprises the catalytic subunit complexed to two other proteins, called ABIN2 and p105. The activation of Tpl2 requires another protein kinase, termed IKK, which phosphorylates the p105 component. This triggers the destruction of p105, thereby releasing Tpl2 from the complex. However, to become active, the Tpl2 catalytic subunit must itself be phosphorylated by another protein kinase distinct from IKK, and which has yet to be identified. The aim of my project is to identify this novel kinase, which may itself turn out to be an important target for the development of anti-inflammatory drugs.
Research Group:
University of Dundee – College of LIfe Sciences
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