The role of tristetraprolin in the suppression of inflammation and cancer

Monocytes and macrophages are white blood cells that play critical roles in defence against pathogens, repair of injury and maintenance of organ function. Many of the genes that these cells express have anti-microbial effects, but are also potentially harmful to the host if they are expressed for too long, at too high a level, or in the wrong location. For example, excessive production of tumour necrosis factor (TNF) by monocytes or macrophages contributes to rheumatoid arthritis, septic shock and many other chronic and acute inflammatory pathologies. Prof Clark’s group is interested in the negative regulation of TNF and other pro-inflammatory genes in macrophages. There are two principal reasons for this interest. The first is that defects in negative regulatory mechanisms cause inappropriate expression of pro-inflammatory factors. Greater knowledge of these mechanisms will help us to understand the pathogenesis of inflammatory diseases. The second reason is that therapeutic effects can be exerted by engaging these negative control mechanisms to switch off the expression of inflammatory mediators. Several different research projects in the Clark lab are linked to this theme.

Tristetraprolin is an RNA binding protein that negatively regulates expression of TNF and many other mediators of inflammation. The activity of TTP is regulated by a phosphorylation-mediated switch, allowing TTP to control both the on- and off-phases of expression of inflammatory mediators [1]. We recently generated a knock-in mouse line in which TTP is permanently active as a negative regulator of inflammatory genes, because its phosphorylation is blocked [2]. The knock-in mouse is highly resistant to pro-inflammatory challenges [2-4]. We are interested in how the constitutively active form of TTP prevents inflammation, and whether it functions in cells other than macrophages. We want to explore the concept of activating TTP to inhibit inflammation, as our preliminary data suggest may be possible [3]. This could ultimately lead to the development of a novel class of anti-inflammatory drugs. We want to investigate whether phosphorylation and inactivation of TTP is a biomarker of chronic inflammation in man [3], and if so, to identify the mechanisms responsible. There are some very interesting data suggesting that either down-regulation or inactivation of TTP may promote tumour progression [5]. We wish to explore whether, conversely, the activation of TTP might prevent tumour progression. Finally, we wish to identify whether there might be harmful consequences of promoting the activation of TTP, for example increased susceptibility to infection.

Person Specification
Applicants should have a strong background in immunology, and ideally a background in molecular biology. They should have a commitment to research in inflammation and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply
Informal enquiries should be directed to Prof. Andy Clark ([Email Address Removed]).
To apply, please send the following to Prof Andy Clark [Email Address Removed]:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.