PI 3-kinase isoform-specific-signalling in macrophages.

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PI3-kinases (PI3Ks) generate lipid second messenger signals that control cell growth, proliferation, survival, intracellular traffic, cytoskeletal changes and cell migration. There is strong evidence for an important role of these enzymes in inflammation, autoimmunity, cancer and diabetes. Mammals have 8 distinct PI3K isoforms, most of which have poorly defined individual roles in cells and in the organism. This research proposal seeks to uncover the roles of PI3K isoforms at the cellular level, using genetic and pharmacological approaches. Focus will be on the PI3Ks that are regulated by tyrosine kinase- or G protein-coupled receptors. As a cell model, we will use primary macrophages derived from gene-targeted mice in which PI3K isoforms have been inactivated in a constituted or conditional manner. In addition, newly developed isoform-specific PI3K inhibitors will be tested for their effects on macrophage biology. Our main aims are to uncover the signalling programmes that are controlled by the individual PI3K isoforms in cell migration and cell polarity. We also aim to establish immortalised macrophage cell lines with mutant PI3Ks, which will be invaluable resources for the further development of isoform-specific PI3K inhibitors. In summary, this project addresses fundamental cell biology questions and will also provide important information for drug development and a better understanding of disease processes such as inflammation, autoimmunity and cancer.