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Cell autonomous role of beta3 integrin: function in macrophages (Macrophage Itgb3)
Date du début: 1 sept. 2013, Date de fin: 31 août 2017 PROJET  TERMINÉ 

Integrins play a key role in the binding of cells to the extra-cellular matrix, cell migration, cell-cell adhesion and cell-cell signaling. The ß3-integrin subunit is expressed in a wide range of tissues. β3 integrins occur i.e. as αvβ3 in various cell types but as αIIβ3 exclusively in megakaryo/-thrombocytes. Mice with a germline β3 integrin deficiency (β3-/-) show enhanced tumor growth and neoangiogenesis due to angiogenic signaling in endothelial cells, and are prone to systemic inflammation and atherosclerosis on high fat diet despite a severe bleeding predisposition. Based on the complex results from germline gene targeting and antibody based loss of function experiments, a cell-autonomous role of the β3 integrin is very likely. I have demonstrated that bone marrow derived β3 integrin is strongly implicated in diet induced pneumonitis, atherosclerosis and death in hyperlipidemic β3 integrin-deficient mice vivo supporting the hypothesis that β3 integrin-dependent signaling in macrophages may be anti-inflammatory. In this proposal, I would like to study the cell-specific role of β3 integrin in macrophage populations. The susceptibility to high-fat diet induced inflammation will be investigated employing newly generated mice that allow the tissue-specific deletion of the β3 integrin combined with the possibility of following the beta3 integrin expression in macrophages in vivo on the basis of a fluorescent marker. We will utilize high-throughput technologies to identify and reconstruct molecular pathways associated with β3 integrin deficiency in macrophages with regards to inflammation and atherogenesis. We will also test whether the rescue of macrophage specific expression of β3 integrin is sufficient to correct the β3 integrin deficient phenotype. Knowledge about the cell-specific function of β3 integrin is important for clinical use of non-selective β3 integrin antagonists and may illuminate novel molecular pathways in (vascular) inflammation and cancer.