HIF-1α通过TSHR介导的TSH作用调节Th17细胞分化在桥本氏甲状腺炎（HT）中的作用研究

Hashimoto's thyroiditis (HT) is mainly caused by the thyroglobulin-specific T-cell infiltration, the thyroid is damaged obviously resulting in hypothyroidism. The peripheral blood of Hashimoto's thyroiditis patients has increased Th17 cell differentiation, increased secretion of IL-17, IL-22. Recent studies, hypoxia-inducible factor 1 (HIF-1) regulates the balance between regulatory T cell (Treg) and TH17 differentiation, enhancing TH17 development. Hypoxia-induced active signal transducer and activator of transcription3(STAT3) accelerated the accumulation of HIF-1αprotein, while (STAT3) enhancing TH17 development. TSH receptor (TSHR) is widely expressed in lymphocytes, relative hypoxia exists in Hashimoto's thyroiditis with increased expression of TSH.TSH activates the Janus kinases(JAK)/signal transducer and STAT3 pathway via TSHR. Inferred above, HIF-1α regulate Th17 cell differentiation play a role in Hashimoto's thyroiditis pathogenesis, which may be caused by TSHR-mediated TSH effect. The project intends to silence TSHR and HIF-1α expression, from clinical specimens, cell models and animal models, exploring the TSHR-mediated TSH role of HIF-1α regulate Th17 cell differentiation in the pathogenesis of Hashimoto's thyroiditis. This study would provide new understanding of the mechanism in the Hashimoto's thyroiditis, would provide new ideas for prevention and treatment of Hashimoto's thyroiditis.

桥本氏甲状腺炎（HT）主要是由甲状腺球蛋白特异的T细胞浸润破坏甲状腺而导致的甲减。HT患者外周血Th17细胞分化增高，分泌IL-17、IL-22增多。最新报道显示，HIF-1α调节Th17和Treg细胞的分化平衡，促进Th17细胞分化。乏氧激活STAT3，增加HIF-1α蛋白积累，STAT3则可以促进Th17细胞分化。促甲状腺素受体（TSHR）在淋巴细胞广泛表达，而且在HT中相对乏氧，TSH表达升高， TSH与TSHR结合，可以激活JAK/STAT3信号途径。据此推测，HIF-1α调节Th17细胞分化在HT发病过程中发挥作用，而且可能是通过TSHR介导的TSH作用引起的。本项目拟沉默TSHR和HIF-1α的表达，从临床标本、细胞模型及动物模型三个系统，探讨TSHR介导的TSH作用与HIF-1α调节Th17细胞分化在HT中的发病机制。本研究将为HT的发生机理提供新认识，为其防治提供新思路。

桥本氏甲状腺炎（HT）主要是由甲状腺球蛋白特异的T细胞浸润破坏甲状腺而导致的甲减。HT患者外周血Th17细胞分化增高，分泌IL-17、IL-22增多。而又研究显示，HIF-1α调节Th17和Treg细胞的分化平衡，促进Th17细胞分化。乏氧激活STAT3，增加HIF-1α蛋白积累，STAT3则可以促进Th17细胞分化。我们收集了经病理证实为HT患者的外周血和甲状腺组织标本。通过流式细胞术和免疫组织化学发现，Th17细胞比例明显较正常对照升高，并且HIF-1α、pSTAT3表达增强。于是我们推测，HIF-1α调节Th17 细胞分化在HT 发病过程中发挥作用，而且可能是通过TSHR介导的TSH 作用引起的。为了验证此假设，我们在体外诱导分化Th17细胞，并用TSHR和HIF-1αRNA干扰慢病毒感染所诱导分化的Th17细胞。我们体外研究证实了TSH通过与TSHR的作用，上调HIF-1α的表达，调节Th17 细胞分化。并且这种作用是通过上调pSTAT3的表达实现的。最后，我们构建了小鼠自身免疫性甲状腺炎动物模型体内验证了此观点。我们的研究为HT 的发生机理提供新认识，为其防治提供新思路。

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