TRPM7通道参与动脉粥样硬化的机制研究

It is demonstrated that the dysfunction of calcium signal is involved in atherosclerosis. We employed the model of macrophage-derived foam cell to screen the changed calcium channel which located on cell membrance. We found that TRPM7 is significant increased in the cell model compared as the normal cell. Furthermore, silence of TRPM7 channel could decrease calcium influx and prevent the formation of foam cell. The inhibitor of TRPM7 channel could decrease atherosclerosis plaque formation. Base on the preliminary results, the following experiments is designed to investigate: 1) How the silence or overexpression of TRPM7 influence the formation of macrophage-derived foam cell and calcium influx. 2) To explore how the signal CaMKII→Calcineurin→NF-AT influence the expression and activity of SR-A, CD36, ABCA1, et.al. 3) To establish TRPM7 and ApoE double-knockout mice, we will investigate how deficiency of TRPM7 influence the formation of atherosclerosis plaque and explore the molecular machanisms. The study will elucidate the effect of TRPM7 channel on the formation of macrophage-derived foam cell and the development of atherosclerosis, and evaluate whether TRPM7 channel could be use for potential therapeutic target of atherosclerosis.

已报道动脉粥样硬化过程中有钙信号异常，然而由何种钙通道介导尚待揭示。我们用巨噬细胞泡沫化模型筛选到泡沫化过程中TRPM7通道表达显著增加。预实验发现沉默TRPM7减少细胞外Ca2+内流且抑制泡沫化；TRPM7抑制剂能减少apoE基因敲除小鼠的动脉粥样斑块形成。在此基础上，本课题拟: 1）沉默/过表达TRPM7通道，观察TRPM7对巨噬细胞泡沫化脂质积聚的作用；2）考察经TRPM7通道的Ca2+→Calcineurin→NF-AT信号如何调控脂质摄取/排出的相关分子SR-A, CD36及ABCA1等表达和活性；探讨Ca2+信号在泡沫细胞和动脉斑块形成过程中的作用；3）建立TRPM7和ApoE双基因敲除小鼠，考察TRPM7通道对动脉粥样斑块形成的影响及分子机制。以阐明TRPM7在动脉粥样斑块形成中的作用，为评估TRPM7通道能否作为防治动脉粥样硬化的新靶点提供依据。

研究项目如期实行，我们用巨噬细胞泡沫化模型筛选到泡沫化过程中TRPM7通道表达显著增加，发现沉默TRPM7减少细胞外Ca2+内流且抑制泡沫化；过表达该基因可促进巨噬细胞泡沫化，TRPM7抑制剂能减少apoE基因敲除小鼠的动脉粥样斑块形成。探讨Ca2+信号在泡沫细胞和动脉斑块形成过程中的作用；建立TRPM7和ApoE双基因敲除小鼠，考察TRPM7通道对动脉粥样斑块形成的影响及分子机制。以阐明TRPM7在动脉粥样斑块形成中的作用，为评估TRPM7通道能否作为防治动脉粥样硬化的新靶点提供依据。