The tyrosin kinase Syk: A potential therapeutic target in atherosclerosis

炎症是动脉粥样硬化形成的核心机制。然而，到目前为止，抗炎治疗尚未被引入到动脉粥样硬化的临床治疗中。申请人之前的工作确定了酪氨酸激酶Syk-炎症信号的中心分子-作为动脉粥样硬化治疗干预的潜在新靶点。一方面，Syk抑制剂福斯塔替尼减少了动脉粥样硬化小鼠新斑块的产生。同样，福斯塔替尼可抑制脾和骨髓中炎性单核细胞的产生。然而，当使用Syk抑制剂时，一个令人担忧的问题是非特异性影响。因此，了解分子机制是至关重要的，本提案将利用最先进的条件性和选择性基因敲除小鼠深入研究Syk激酶在动脉粥样硬化中的作用。特别是以下问题将被解决：1)Syk基因可诱导的普遍缺失是否限制了动脉粥样硬化的发生？2)哪些细胞类型介导了Syk对动脉粥样硬化的依赖效应？3)Syk的条件性基因缺失如何影响已建立的动脉粥样硬化病变的进展和/或消退(两种情况都模拟了临床情况)。对于上述所有研究，我们将进一步研究其涉及的机制。具体地说，我们将测试基因Syk缺失是否影响单核细胞的造血和分化、炎症细胞的迁移以及斑块中细胞的凋亡和增殖。最后，通过翻译的方法，我们将测试Syk的激活是否在患有或不患有冠心病的患者中改变细胞类型。这一提议产生的发现将极大地有助于理解Syk在动脉粥样硬化中的生理作用，并促进新的和特定的治疗应用的开发。

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.