雷帕霉素复合物1在巨噬细胞炎症反应中的作用与机制研究

Atherosclerosis (AS) is a chronic vascular inflammatory diseases. Type II diabetes as an independent risk factor for atherosclerosis, play an important role in its development. Our preliminary experiments found that rapamycin complex 1 (mTORC1) expression was significantly increased in the monocytes and macrophages of Type II diabetes mouse model; Administration of mTORC1 inhibitor can suppress the size of atherosclerotic plaque in western type diet fed LDLR-/ - mice. Therefore, we propose the following hypothesis: mTORC1 can increase the conversion of monocytes to macrophages and promote macrophages to produce inflammatory cytokines which affects the progress of AS. In order to prove this hypothesis, we will clarify the role of mTORC1 in macrophage activation and polarization by activating or inhibiting mTORC1; further, we will observe the production of inflammatory cytokines, cell migration and cell adhesion with genetic or drugs means of activation or inhibition of mTORC1 in the activated macrophage and reveal the underlying mechanism. Finally, we will do the bone marrow transplantation in mouse AS model, in order to clear the role of macrophages mTORC1 in the progression of AS. Through this project, we expect to be able to reveal the role of mTORC1 in macrophage activation, macrophage inflammatory response, as well as the impact of the AS.

动脉粥样硬化（AS）是一类慢性的血管炎症疾病，II型糖尿病作为动脉粥样硬化独立危险因子，在其发生发展中起到重要作用。预实验发现，雷帕霉素复合物1（mTORC1）在II型糖尿病小鼠模型的单核细胞与巨噬细胞中的表达显著增加；给予mTORC1抑制剂可以抑制高脂饮食下LDLR-/-小鼠动脉粥样硬化的斑块形成。因此我们提出如下假说：mTORC1通过增加单核细胞向巨噬细胞的转化以及促进炎症因子产生而影响AS的进展。为了证明该假说，首先我们通过用基因或药物手段激活或抑制mTORC1，以明确mTORC1在巨噬细胞活化和极化中的作用并进一步在活化的巨噬细胞中观察其对炎症因子产生、细胞迁移和细胞粘附的影响及其机制；最后我们将在AS小鼠模型上进行骨髓移植，以明确巨噬细胞mTORC1对AS形成的作用。通过该项目我们期望能够揭示mTORC1对巨噬细胞活化、巨噬细胞炎症反应以及AS的影响。

II型糖尿病作为动脉粥样硬化独立危险因子，在其发生发展中起到重要作用。胰岛素抵抗是II型糖尿病的主要特征，虽然胰岛素抵抗情况下PI3K/Akt信号减弱，但是mTORC1的活性却显著增加。尽管许多研究提示mTORC1与动脉粥样硬化有直接关联，但是这些研究都局限于全身给药或基因敲除，对于巨噬细胞中mTORC1在动脉粥样硬化的研究尚属空白。为此我们通过研究mTORC1对巨噬细胞的激活，进而引起炎症因子特别是MCP-1的产生和更多巨噬细胞向血管内皮的迁移和粘附，揭示mTORC1在动脉粥样硬化早期病理机制中的作用。我们将建立巨噬细胞特异性mTORC1激活和抑制的动脉粥样硬化模型小鼠，观察其斑块及斑块区域炎症反应情况，并在细胞水平研究单核细胞mTORC1对于巨噬细胞的激活及激活的巨噬细胞mTORC1对炎症反应的影响和机制。本课题不仅加深了对动脉粥样硬化病理生理机制的理解，对发展新的干预和治疗手段也具有重要意义。