G蛋白成员G15在TSH/TSHR信号调控巨噬细胞炎症的作用及其机制

血清TSH升高是亚临床甲减的特征,流行病学调查发现TSH是动脉粥样硬化发生发展的独立危险因素。项目组前期研究发现ApoE敲除小鼠中沉默TSH受体(TSHR)减少动脉粥样硬化病变,降低斑块内巨噬细胞炎症分子表达；体外实验发现TSH刺激巨噬细胞诱发其促炎反应并增加细胞核内HNF-4α含量；沉默G蛋白成员G15的α亚基(Gα15)显著降低炎症通路关键因子IκB的磷酸化水平。然而其机制不清,尚未见相关报道。本项目拟从TSH/TSHR切入,以巨噬细胞为研究对象,围绕TSHR下游的G蛋白信号通路,利用体内实验(建立巨噬细胞特敲Tshr或Gα15小鼠，亚甲减及动脉粥样硬化等模型)和体外实验相结合的手段,研究1.TSH通过HNF-4α调控Gα15的转录机制；2.TSH通过TSHR/G15及其下游PKC信号通路诱发巨噬细胞炎症的分子机制,为阐明动脉粥样硬化发生发展中TSH调控巨噬细胞炎症的理论提供新思路。

Subclinical hypothyroidism (SCH) is characterized by elevated serum TSH, epidemiology data showed that SCH was closely associated with atherosclerosis occurrence and development. Our group has found that Tshr knockout decreased the plaque area and plaque macropahge inflamation in ApoE knockout mice. In vitro assays showed that TSH induced macrophage inflammation and increased nuclear HNF-4α；Gα15 knockdown markedly decreased the phosphorylation of key inflammatory pathway factor IκB . No research on the mechanism has been reported.This study further tries to clarify the role of HNF-4α in the process of TSH regulates Gα15 transcriptionas well as the downstream signal transduction molecules by combining in vivo (macrophage specific Gα15 or Tshr knockout mice, animal models of subclinical hypothyroidism and atherosclerosis) and in vitro study, and provides new insights into the mechanism of TSH promotes macrophage inflammation during atherogenesis.