SIRT3调节T细胞代谢对类风湿关节炎的影响及分子机制研究

Nowadays more and more researchers begin to realize the importance of T cells metabolism in the pathogenetic process of Rheumatoid arthritis (RA). One of the fundamental traits of immune cells in rheumatoid arthritis (RA) is their ability to proliferate which need a lot of energy, implicating metabolic control as a basic disease mechanism. Naive CD4+ T cells from patients with RA have a distinct metabolic signature, characterized by dampened glycolysis, low ATP levels and enhanced shunting of glucose into the pentose phosphate pathway. But the mechanism of who regulates the change of metabolism in RA is little known. SIRT3 plays important roles in cell metabolism, including glycolysis and lipid metabolism, but whether SIRT3 regulates RA process is unknown. Our earlier results showed that SIRT3 decreased in the naïve T cells of RA patients, and PFKFB3, which plays a vital role in glycolysis, was down regulated. And more results demonstrated that SIRT3 indeed participated in the activation of T cells . Therefore we want to find the effects of SIRT3 in the pathogenetic process of RA and its underlying molecular mechanisms .We plan to utilize SIRT3 knockout mice and collagen induced arthritis model, and ex vivo experiments to explore the effects of SIRT3 in regulating T cell metabolism and RA process. This project will help to understand the underlying mechanisms of cell metabolism in RA and will give new clue to drug development.

T细胞代谢在类风湿关节炎（RA）发生中的作用逐渐被重视，RA患者T细胞中糖酵解关键酶PFKFB3等表达下降，糖酵解不足，致使ATP生成减少，最终导致T细胞异常增殖和凋亡，但 PFKFB3等代谢酶的上游调控机制仍不清楚。而SIRT3作为代谢调控的重要蛋白，参与调节糖代谢等多个生物学过程，但SIRT3在RA发生中的作用还未见报道。我们前期研究发现，RA患者幼稚T细胞中，SIRT3表达明显下降，并且代谢相关调控因子尤其糖酵解关键酶PFKFB3显著下降。并通过体外实验证明，SIRT3确实参与T细胞活化的代谢转变过程。因此我们拟通过利用SIRT3敲除鼠并构建胶原诱导关节炎模型，以及体外过表达/敲低SIRT3实验，进一步深入探索SIRT3对T细胞代谢的影响及在RA发生中的作用和分子机制。本研究有助于深入阐释T细胞代谢在RA发生中的调控机制，也为寻找RA治疗措施提供新思路。

T细胞代谢在类风湿关节炎（RA）发生中的作用逐渐被重视，而SIRT3作为代谢调控的重要蛋白，参与调节糖代谢等多个生物学过程，但SIRT3在RA发生中的作用还未见报道。我们通过体外实验证明，细胞中敲低SIRT3后，T细胞凋亡增多, 而ATP生成显著下降，乳酸生成降低，说明SIRT3敲低后糖酵解过程可能受阻。我们进一步利用SIRT3敲除鼠并构建胶原诱导关节炎模型，以及体外过表达/敲低SIRT3实验，证明SIRT3敲除后，关节炎严重程度明显上升，并且关节软骨显著破坏。随后我们用SIRT3敲除T细胞进行RNA-seq测序，结果显示代谢相关通路异常，尤其糖酵解代谢下降，并且糖酵解重要调控酶PFKFB3表达明显下降。为了进一步明确PFKFB3在SIRT3调控T细胞代谢和RA发生中的作用，我们在SIRT3敲除T细胞和对照T细胞中，过表达了PFKFB3，发现过表达PFKFB3，可以在一定程度上拮抗SIRT3缺失造成的T细胞代谢改变。证明SIRT3可能通过调节PFKFB3表达，来进一步调控T细胞代谢以及RA的发生发展。本项目总体上发表标注基金号的SCI文章3篇，其中IF>8分的文章2篇，其中有1篇影响因子大于10。