The tyrosin kinase Syk: A potential therapeutic target in atherosclerosis

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Inflammation is a central mechanism in atherogenesis. However, so far anti-inflammatory therapies have not been introduced into the clinical therapy of atherosclerosis. Previous work of the applicant identifies the tyrosinkinase Syk - a central molecule in inflammatory signaling - as a potential new target for therapeutic intervention in atherosclerosis. On the one hand the Syk inhibitor Fostamatinib reduces the generation of new plaques in atherosclerotic mice. In line, Fostamatinib inhibits the generation of inflammatory monocytes in spleen and bone marrow. A concern when using Syk inhibitors are however unspecific effects. It is therefore vital to understand the molecular mechanism and this proposal will investigate in depth the role of Syk kinase in atherosclerosis employing state of the art conditional and selective knockout mice. Particularly the following questions will be addressed: 1) Does the genetic inducible ubiquitary deletion of Syk limit the de novo atherogenesis? 2) Which cell types mediate Syk dependent effects on atherogenesis? 3) How does the conditional genetic deletion of Syk impact the progression and/ or regression of established atherosclerotic lesions (both scenarios mimic the clinical situation). For all above studies we will further study the mechanism involved. Specifically we will test whether the genetic Syk deletions impact the hematopoiesis and differentiation of monocytes, the migration of inflammatory cells as well as the apoptosis and proliferation of cells in the plaque. Finally, with a translational approach we will test if Syk activation is altered cell-type dependent in patients with or without coronary heart disease. The findings generated by this proposal will highly contribute to the understanding of the physiological role of Syk in atherosclerosis and facilitate the development of new and specific therapeutic applications.