Research objectives and content During the inflammatory response, cytokines such as Tumor Necrosis Factor (TNF) transiently upregulate in endothelial cells (EC) a set of genes encoding, amongst others, cell adhesion molecules and chemokines that together mediate the interaction of the endothelium with cells of the immune system. Infiammatory gene upregulation seems to be mediated predominantly by the transcription factor NF-kB, and when deregulated, the whole process is thought to play a central role in the perpetuation and chronicity of important inflammatory conditions.
In the proposed study, we will test the concept of NF-kB being a central mediator of inflammation and we will attempt to inhibit in vivo inflammatory responses in transgenic mouse lines which will be engineered to overexpress transdominant forms of I kappa B alpha (mIKBa) in EC. To avoid possible developmental deleterious consequences to the physiology of the animal, temporally controlled EC-specific activation of the mIlcBa transgene will be engineered by the use of inducible Cre-loxP methodology. A number of TNF transgenic mouse lines representing models of chronic inflammation already exist in the host laboratory and in combination with the mI-kBa transgenic mice they should be very useful tools in understanding mechanisms of NF-kB interference with EC activation and homeostasis.
Training content (objective, benefit and expected impact)
The aim objective is to learn the methodology involved in generating genetically modified transgenic mice in one of Europe's leading transgenic research laboratories. This will be of benefit to my career development helping to obtain my doctoral degree and subsequent employment as a post-doctoral researcher.
Links with industry / Industrial relevance (22)