TAB1介导糖代谢在糖尿病肾病巨噬细胞极化中的作用机制

Inflammation mediated by macrophage plays a vital role in the development of diabetic nephropathy (DN), and recent sudies have shown that different metabolic profile of glucose determines polarization phenotype of macrophage. Our previous studies found that the increased expression of TAB1 and NF-κB under the treatment of high glucose and advanced glycation end products (AGEs) promotes the activation of M1 macrophage. however, the mechanisms are still poorly understood up to now. Our pre-experiment results showed that TAB1 induces the expression of glycolytic enzymes HK1, PFKFB3, PKM2, LDHA . Thus we suppose that TAB1 induced NF-κB translocates into nucleus and activates hypoxia inducible factor (HIF-1α). Then HIF-1α promotes glycolytic enzymes expression which leads to activation of M1 macrophage and the progression of DN disease. Here, we will study the role of TAB1 played in macrophage polarization of DN disease and clarify the role and mechanism of TAB1/NF-κB/HIF-1α pathway played in glucose metabolism and macrophage polarization through in vivo assay (macrophage specifical TAB1 gene knockout mice, bone marrow transplantation mice, RNA interference in vivo) and in vitro assay (gene overexpression and silence of TAB1 in macrophage). Thus we can provide new strategy with scientific basis in order to treat and control DN disease.

巨噬细胞极化介导的炎症是糖尿病肾病 (diabetic nephropathy, DN)发生的关键因素。晚近研究表明不同的糖代谢方式决定巨噬细胞的极化方向。前期研究证实高血糖、AGEs等显著上调巨噬细胞中TAB1/NF-κB的表达从而促进M1型巨噬细胞激活，但具体机制未明。预实验发现TAB1可以介导HK1, PFKFB3, PKM2, LDHA等糖代谢酶水平升高。因此，我们假设TAB1促进NF-κB入核激活低氧诱导因子(HIF-1α)，上调糖代谢酶表达促进M1型巨噬细胞激活，从而促进DN的发生、发展。本项目由TAB1切入，以影响DN的巨噬细胞极化为主要研究对象，应用体内实验（TAB1基因敲除，骨髓移植，RNA干扰等多种动物模型）和体外实验（TAB1基因沉默和过表达）相结合的方法，阐明TAB1/NF-κB/HIF-1α通路调控糖代谢途径在DN巨噬细胞极化中的作用及机制，为DN防治提供新策略。

晚近研究表明不同的糖代谢方式决定巨噬细胞的极化方向。前期研究证实高血糖等显著上调巨噬细胞中TAB1/NF-κB的表达从而促进M1型巨噬细胞激活，但具体机制未明。本项目由TAB1切入，以影响DN的巨噬细胞极化为主要研究对象，应用临床肾活检标本、体内实验（TAB1基因干扰动物模型）和体外实验（TAB1基因沉默）相结合的方法，TAB1促进NF-κB入核激活低氧诱导因子(HIF-1α)，上调糖代谢酶表达促进M1型巨噬细胞激活，阐明TAB1/NF-κB/HIF-1α通路调控糖代谢途径在DN巨噬细胞极化中的作用及机制，为DN防治提供新策略。