GHR信号通路调控Treg细胞分化在肥胖相关慢性炎症反应中的作用及机制研究

慢性炎症反应是肥胖相关代谢性疾病发生发展的重要因素。调节性T细胞（Treg）作为负向调节炎症反应的核心备受关注，但对Treg的调控机制尚不完全明确。前期研究发现生长激素受体缺陷（GHRKO）小鼠外周血Treg比例升高，脂肪组织M1型巨噬细胞浸润减少，胰岛素敏感性增加。体外GHRKO-Treg细胞诱导效率及Foxp3表达增加，RNAseq发现此细胞内PI3K/AKT信号通路表达下降，该通路及下游mTOR可调控细胞能量代谢，提示GHR可能通过PI3K/AKT/mTOR通路调控Treg细胞能量代谢影响其分化，进而影响肥胖相关慢性炎症反应及代谢紊乱。本研究拟构建高脂饮食肥胖动物模型和体外诱导Treg细胞模型，使用Cre-Loxp靶基因敲除、Treg细胞转输和细胞能量代谢调控等手段，明确GHRKO对Treg分化的作用及其对肥胖相关慢性炎症反应的影响，为代谢性疾病的免疫治疗提供新思路。

Chronic inflammation plays an important role in the obesity related metabolic diseases. The regulatory T cells (Treg) have attracted much attention as the core in negative regulation of inflammation, but the mechanism of regulation on Treg is still unclear. Previous studies found that growth hormone receptor knockout (GHRKO) mice had an increase of Treg proportion in peripheral blood, a reduction of M1 macrophages infiltrated in adipose tissue, and increased insulin sensitivity. The induction efficiency of GHRKO-Treg and the Foxp3 expression in it were higher in vitro. The results from RNAseq showed PI3K/AKT signaling pathway was decreased in GHRKO-Treg, this pathway together with its downstream mTOR can regulate cell energy metabolism, which suggests that GHR may affect the differentiation of Treg cells by regulating cellular energy metabolism through PI3K/ AKT /mTOR signaling pathway, and then affect obesity related chronic inflammation and metabolic disorders. We design to clarify the effect and mechanism of GHRKO on Treg differentiation and its role in obesity related chronic inflammation, by means of diet induced obesity model in vivo, Treg cell induced system in vitro, using methods of knockout target gene with Cre-Loxp system, experiment of Treg cells transfer, and the methods of regulating on cellular energy metabolism. It is expected to provide a new idea of immunotherapy for metabolic diseases.