二肽基肽酶抑制剂通过小异二聚体伴侣调节炎症反应的机制研究

Dipeptidyl peptidese-4 (DPP-4) inhibitor is widely used to treat type 2 diabetes. Previous evidence suggested that DPP-4 inhibitor is involved in the process of inflammation, but the underlying mechanism has not been fully recognized. Our previous work showed that small heterodimer partner (SHP) is the potential binding target of vildagliptin. Furthermore, SHP also plays an important role in the regulation of inflammation. In order to clarify whether there is an interaction between vildagliptin with SHP and whether the interaction is involved in inflammation responses, our research is going to explore the effect of vildagliptin on the level of cytokines in SHP+/+ and SHP-/- mouse model and macrophage. Furthermore, in the inflammation models induced by lipopolysaccharides and oxidatized low-density lipoproteincholesterol, we are going to detect the expression of proteins in Toll like receptor-4/nuclear factor-κB and NOD-like receptors 3 signal pathway.

二肽基肽酶-4（DPP-4）抑制剂是临床中应用广泛的降糖药物，且诸多证据表明DPP-4抑制剂具有抗炎症反应作用，但相关机制尚未完全明确。申请人前期研究发现小异二聚体伴侣（SHP）是DPP-4抑制剂维格列汀的潜在结合靶点，而SHP在炎症反应中同样发挥着重要的作用。鉴于此，本研究拟建立SHP基因敲除型小鼠模型，分别在SHP+/+和SHP-/-小鼠模型、巨噬细胞中观察维格列汀对炎症因子的影响，进一步建立脂多糖和氧化低密度脂蛋白炎症模型，研究炎症因子的变化以及Toll样受体4/核因子-κB和NOD样受体家组蛋白3信号通路中蛋白质表达的差异，阐明维格列汀是否通过与SHP的相互作用参与炎症反应。本研究的实施将有助于发现DPP-4抑制剂调节炎症反应的机制。

二肽基肽酶-4（DPP-4）抑制剂是临床中应用广泛的降糖药物，诸多证据表明DPP-4抑制剂具有抗炎症反应作用，但相关机制尚未完全明确。前期研究发现小异二聚体伴侣（SHP）是DPP-4抑制剂维格列汀的潜在结合靶点，而SHP在炎症反应中同样发挥着重要的作用。本研究通过建立SHP基因敲除型小鼠模型，分别在SHP+/+和SHP-/-小鼠模型、巨噬细胞中观察维格列汀对炎症因子的影响，进一步建立脂多糖和氧化低密度脂蛋白炎症模型，研究炎症因子的变化以及Toll样受体4 (TLR4) /核因子-κB (NF-κB) 和NOD样受体家组蛋白3 (NLRP3) 信号通路中蛋白质表达的差异，阐明维格列汀是否通过与SHP的相互作用参与炎症反应。本研究结果发现维格列汀可减轻小鼠体内炎症反应；基因敲除SHP增加炎症反应，应用维格列汀可以部分缓解；LPS剂量依赖性增加炎症反应，这一过程不完全依赖于SHP基因，维格列汀可部分缓解LPS诱导的炎症反应。TLR4/NF-κB及NLRP3通路在上述炎症反应中发挥作用。

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