Pim-2调控mTOR信号在动脉粥样硬化炎症机制中的作用研究

Nowadays, atherosclerosis(AS) is one of the most frequent cardiovascular disease, which is a major public health problem in the world. Lipid and inflammatory cell infiltration were the accepted mechanism of AS. It was reported that mTOR signal was an important pathway in AS, our previous studies evidenced that Pim-2 as a cardioprotective protein to against hypoxia/ reoxygenation injury. Pim-2 also played a role in inflammation via mTOR pathway. Base on these, we put forward the hypothesis that Pim-2 can also act an anti-inflammatory mechanism to reverse AS development, and the mTOR signal is the specific mechanism. We propose to apply series experiments in vitro and in vivo, such as ApoE-/- AS animal model, macrophage foam cell model, immunohistochemical, Elisa, over-expression Pim-2 and inhibitory mTOR to verify the anti-inflammatory mechanism of Pim-2 in AS. In short, this study will make a useful exploration to verify the theory that Pim-2 has anti-inflammatory effect in AS and Pim-2 was a new cardioprotective protein.

心血管疾病是重大公共卫生问题，其中动脉粥样硬化(AS)性疾病是重中之重。脂质浸润，炎症细胞侵袭是AS的主要机制。研究证实mTOR信号参与了AS的发生发展，我们前期发现Pim-2能抵抗缺氧复氧损伤而保护心肌细胞，ox-LDL处理巨噬细胞时，炎症因子表达升高，Pim-2、mTOR表达上调，基于Pim-2具抗炎作用，因此我们假设Pim-2也能通过抗炎机制来逆转AS的发生发展，mTOR信号可能是其发挥AS抗炎作用的机制。我们将通过建立Apo E基因敲除AS动物模型及巨噬细胞源性泡沫细胞模型，检测AS条件下Pim-2，mTOR及相关炎症因子的表达，并采用免疫组化、过表达及沉默Pim-2基因及抑制或激活mTOR信号的方法来验证这一假说。通过本项目的研究，我们将证实Pim-2通过调控mTOR信号通路减轻炎症反应而逆转AS，为深入了解AS炎症机制及Pim-2作为新型心血管保护因子提供更多的依据。

Pim-2具心肌保护及抗炎作用，本项目通过建立Apo E基因敲除AS动物模型及.使用ox-LDL处理类巨噬细胞诱导泡沫细胞模拟体内动脉粥样硬化微环境，发现AS条件下Pim-2、mTOR及其下游分子表达明显增加，且炎症因子表达亦增加。在体动物模型及离体细胞实验结果显示过表达Pim-2时炎症因子表达下降、AS减轻，mTOR及其下游因子表达受抑制，而沉默Pim-2基因时炎症因子表达明显增加、AS程度加重，同时mTOR及其下游因子表达明显增加。有趣的是加用mTOR信号激动剂MHY1485能抵消过表达Pim-2的抗动脉粥样硬化及抗炎作用，而加用mTOR信号抑制剂雷帕霉素能挽救Pim-2沉默时的促动脉粥样硬化及促炎作用。另外在Pim-2沉默时干扰掉mTOR或Raptor发现Pim-2促AS作用消失，炎症因子表达下降，因此说明Pim-2通过抑制炎症抗AS的通路是mTORC1。综上所有结果，本研究证实Pim-2通过调控mTORC1抑制炎症来逆转AS，同时为Pim-2作为新型心血管保护因子提供更多的依据。项目资助发表SCI论文4篇，中文核心1篇。培养研究生4名，其中博士2名，硕士2名。项目投入经费40.8万元，间接经费6.8万元，支出28.7万元，各项支出基本与预算相符，剩余经费5.3万元，剩余经费计划用于本项目研究后续支出。

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