亲环素D在高脂饮食诱发的甲状腺球蛋白表达下调中的作用及机制

In recent studies, lipotoxicity was proved to be a risk factor of hypothyroidism, while the involved mechanism has not been fully elucidated. Thyroglobulin (Tg), a key molecular of thyroid hormone synthesis, is closely related to hypothyroidism. Our previous research found that serum thyroid hormone levels, as well as thyroglobulin expression were decreased in wild-type mice fed with high-fat diet. Interestingly, the above phenomenon was not observed in cyclophilin D (CypD)-deficient mice, which indicates that CypD might mediate hypothyroidism induced by high-fat diet. Taking CypD as a starting point, the present study will elucidate the following aspects: 1. the effects of CypD in the decreased thyroglobulin expression induced by high-fat diet; 2. the molecular mechanism by which CypD is regulated by HAX-1 and Hsp90. Both in vivio (thyroid specific CypD knockout mice model) and in vitro (gene mutation, etc.) experiments will be used. The study aimed to further demonstrate the mechanism of thyroid dysfunction induced by lipotoxicity, and provide new strategies for the prevention and treatment of hypothyroidism.

脂毒性可诱发甲状腺功能减退症，但其机制尚未完全阐明。甲状腺球蛋白（Tg）是甲状腺激素合成重要分子，其表达或功能异常与甲减发生密切相关。亲环素D（CypD）是调节线粒体mPTP孔开放的关键分子。项目组前期动物实验发现，CypD基因敲除可缓解高脂饮食诱发的Tg表达下调及甲状腺激素水平紊乱，提示CypD可能在调控Tg表达中发挥重要作用，但机制尚不明确。本项目拟以CypD为切入点，应用体内实验（关键基因器官特异性敲除等模型）与体外实验（基因突变质粒转染、免疫共沉淀、竞争性蛋白结合ELISA等技术）相结合的方法，从整体、细胞及分子水平：1.明确CypD在高脂饮食诱发的Tg表达变化中的作用；2.阐明HAX-1影响Hsp90/CypD复合体形成，调控下游Tg表达的机制。项目旨在阐明脂毒性诱发Tg表达下调的分子机制，为临床防治甲状腺疾病提供新的思路。

脂毒性可诱发甲状腺功能减退症，但其机制尚未完全阐明。甲状腺球蛋白（Tg）是甲状腺激素合成重要分子，其表达或功能异常与甲减发生密切相关。亲环素D（CypD）是调节线粒体mPTP孔开放的关键分子。项目组前期动物实验发现，CypD基因敲除可缓解高脂饮食诱发的Tg表达下调及甲状腺激素水平紊乱，提示CypD可能在调控Tg表达中发挥重要作用，但机制尚不明确。本项目以CypD为切入点，应用体内实验（甲状腺特异性敲除CypD基因小鼠模型）与体外实验（基因突变质粒转染、免疫共沉淀等技术）相结合的方法，从整体、细胞及分子水平：1.明确了CypD介导的线粒体氧化应激与甲状腺Tg表达下调密切相关；2.初步探明了HAX-1可影响Hsp90/CypD复合体形成，进而调控下游Tg表达的机制。本项目初步阐明脂毒性诱发Tg表达下调的分子机制，为临床防治甲状腺疾病提供新的思路。