Pro-inflammatory S100A12 in atherosclerosis and acute coronary syndrome

描述（由申请人提供）：我对动脉粥样硬化相关血管紊乱的机制感兴趣，特别是在促炎S100/ calgranulins蛋白的贡献。在人类动脉粥样硬化血管以及冠心病猝死的糖尿病患者的冠状动脉斑块中发现了S100 A12，提示其在动脉粥样硬化和斑块不稳定中起作用。血清S100A12浓度升高存在于慢性炎性疾病患者，包括血管炎患者，如川崎病和糖尿病患者。S100A12促进炎症的一种机制是通过激活晚期糖基化终产物（RAGE）受体，RAGE是一种与血管功能障碍和动脉粥样硬化密切相关的受体。具体来说，我之前表明RAGE是S100A12的中心细胞表面受体，导致内皮细胞和巨噬细胞的激活，这些细胞在持续炎症和血管功能障碍中起关键作用。我提议通过构建两种转基因小鼠模型来验证S100A12加速动脉粥样硬化的假设，分别使用SM22-a启动子靶向平滑肌细胞和CD11b启动子靶向巨噬细胞表达S100A12。将研究两种血管功能障碍模型：首先，我将检查血管对动脉损伤模型的反应，因为有证据表明S100A12调节平滑肌细胞的增殖和迁移。其次，我将S100A12转基因小鼠与动脉粥样硬化易感ApoE缺失小鼠杂交，并在不同时间点进行评估。我预计S100A12将加速动脉粥样硬化的发展，我将检查S100A12是否以rage依赖和rage独立的方式介导这些作用。为了验证这一假设，S100A12小鼠将与RAGE null和RAGE/ApoE双null小鼠杂交。这些实验将揭示S100A12的促炎和促血栓作用机制，并将为这些蛋白是否可能作为开发治疗动脉粥样硬化新药的重要细胞靶点提供信息。

DESCRIPTION (provided by applicant): I am interested in mechanisms of vascular disturbances related to atherosclerosis, specifically in the contribution of the pro-inflammatory S100/ calgranulins proteins. S100 A12 was identified in human atheromatous vasculature as well as in the coronary plaque of diabetic patients with sudden coronary death suggesting a role in atherosclerosis and plaque destabilization. Increased serum S100A12 concentrations are present in patients with chronic inflammatory diseases including patients with vasculitis such as Kawasaki disease and in diabetic patients. One mechanism by which S100A12 promotes inflammation is by activation of the receptor for Advanced Glycation Endproducts (RAGE), a receptor strongly linked to vascular dysfunction and atherosclerosis. Specifically, I previously showed that RAGE is a central cell surface receptor for S100A12 leading to activation of endothelial cells and macrophages, cells critically involved in sustained inflammation and vascular dysfunction. I propose to test the hypothesis that S100A12 accelerates atherosclerosis by generating two transgenic mouse models with S100A12 expression targeted to the smooth muscle cells by using the SM22-a promoter and targeted to macrophages by using the CD11b promoter. Two models of vascular dysfunction will be studied: First, I will examine vascular response to a model of arterial injury as there is evidence that S100A12 modulates smooth muscle cell proliferation and migration. Second, I will bred the S100A12 transgenic mice with atherosclerosis prone ApoE null mice and assess at various time points. I expect that S100A12 will accelerate the development of atherosclerosis and I will examine if S100A12 mediates these effects in a RAGE-dependent and in RAGEindependent manner. To test this hypothesis, the S100A12 mice will be bred with the RAGE null and RAGE/ApoE double null mice. These experiments will shed light into the mechanism of pro-inflammatory and pro-thrombotic actions of S100A12 and will provide information on whether these proteins may serve as an important cellular target for the development of new drugs to treat atherosclerosis.