肾组织内巨噬细胞亚型活化与肾间质纤维化进展密切相关，受代谢改变的调控。谷氨酰胺(Gln)代谢紊乱参与纤维化进程。申请者的前期研究证实：Gln缺乏可导致巨噬细胞M2型活化障碍，而不影响M1型活化。近期其他学者发现：Akt-mTORC1可感知谷氨酰胺丰度，通过磷酸化ATP-柠檬酸裂解酶丝氨酸455位点(ACYL S455)上调酶活性，调控M2型活化；而氨基酸缺乏则抑制M2型活化。由此我们提出：Gln代谢紊乱调控M2型巨噬细胞活化是肾间质纤维化进展的重要机制，而ACYL S455极可能是其中的关键代谢调控位点。本项目拟从临床、动物、细胞三个层面，结合基因工程小鼠、底物模仿多肽、点突变等技术，阐明Akt-mTORC1感知Gln代谢紊乱调控巨噬细胞M2亚型活化的分子机制，明确ACYL S455是其中的关键位点，为从氨基酸代谢角度出发探索肾间质纤维化精准治疗新策略提供实验依据。

Macrophage polarization is closely related to the progression of renal interstitial fibrosis, which is regulated by metabolism reprogramming. Glutamine (Gln) metabolic disorder is involved in the process of renal fibrosis. Our previous data have confirmed that Gln deficiency can inhibit the activation of M2 macrophage, without affecting the activation of M1 macrophage. Other recent studies have found that glutamine metabolism regulates M2 activation by phosphorylation of ATP-citrate lyase serine 455(ACYL S455) through Akt-mTORC1 pathway, while amino acid deficiency inhibits M2 macrophage activation. Therefore, we hypothesize that the activation of M2 macrophage regulated by Gln metabolic disorder is the important mechanism in the progression of renal interstitial fibrosis, and ACYL S455 may be the key metabolic regulatory site. This project will try to clarify the mechanisms of M2 macrophage activation regulated by glutamine metabolic disorder through Akt-mTORC1 and the key role of ACYL S455 in this process, which will provide the experimental evidence for the new therapeutic strategies of renal fibrosis.