谷草转氨酶（Got1）在巨噬细胞分化中的作用

谷氨酰胺代谢对巨噬细胞的极化很重要，但是谷氨酰胺代谢通路是如何调控巨噬细胞的极化以及是否可以通过调控谷氨酰胺代谢通路上的某些关键步骤从而调控巨噬细胞的抗肿瘤免疫活性仍不清楚。我们的初步结果表明巨噬细胞中Got1（谷草转氨酶1）控制着巨噬细胞的极化，Got1的缺陷会增强M1型巨噬细胞的极化，抑制M2型巨噬细胞的极化。非靶向代谢组学的结果表明Got1的缺陷会引起α-KG的降低，和succinate的聚集。本研究中，我们将要使用代谢流分析的方法进一步证明Got1的缺陷是如何引起这些代谢物的异常变化，并将探讨这些差异代谢物是如何调控巨噬细胞的极化，以及巨噬细胞中Got1的缺陷是否引起抗肿瘤免疫反应，是否能增强免疫检查点疗法的效率，最终证明Got1是一个优良的药物靶点。

Glutamine is important for macrophage polarization, however, how glutamine metabolic pathway controls macrophage polarization and if targeting some key step(s) in glutamine pathway could be used to control antitumor activity of macrophage is still largely unknown. Our initial data show that Got1 is critical for macrophage polarization and Got1 deficiency suppresses differentiation of M2 macrophage, and promotes M1 macrophage polarization. Untargeted metabolomics analysis shows that Got1 deficiency leads to decreased level of α-KG and accumulation of succinate. We will use flux analysis to explore how Got1 deficiency leads to differential metabolites, and demonstrate how these differential metabolites regulate polarization of macrophage. We will further determine whether Got1 deficiency in macrophage could enhance antitumor immunity of macrophage and if inhibition of Got1 could synergize with anti-PD1 to increase the efficiency of cancer immunotherapy.