The tyrosin kinase Syk: A potential therapeutic target in atherosclerosis

酪氨酸激酶 Syk：动脉粥样硬化的潜在治疗靶点

• 批准号: 366904753
• 负责人: Professor Dr. Andreas Zirlik
• 金额: --
• 依托单位: Abteilung für Kardiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/366904753?language=en
• 关键词: tyrosin; kinase; Syk; potential; therapeutic

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.

炎症是动脉粥样硬化发生的主要机制。然而，迄今为止，抗炎疗法尚未被引入动脉粥样硬化的临床治疗。申请人之前的工作确定了酪氨酸激酶Syk -炎症信号传导的中心分子-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Fostamatinib减少动脉粥样硬化小鼠新斑块的产生。因此，Fostamatinib抑制脾脏和骨髓中炎性单核细胞的产生。然而，使用Syk抑制剂时需要注意的是其非特异性效果。因此，了解其分子机制是至关重要的，本提案将利用最新的条件和选择性敲除小鼠深入研究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)基因诱导的Syk泛素缺失是否限制了动脉粥样硬化的重新发生？2)哪些细胞类型介导了Syk依赖性的动脉粥样硬化作用？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，我们将进一步研究所涉及的机制。具体来说，我们将测试Syk基因缺失是否会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，通过翻译方法，我们将测试Syk激活是否在有或没有冠心病的患者中改变细胞类型依赖性。该研究结果将有助于了解Syk在动脉粥样硬化中的生理作用，并促进新的特异性治疗应用的发展。