垂体及下丘脑Ⅱ型脱碘酶泛素化修饰在慢性碘过量致TSH升高中的作用及机制研究

项目名称： 垂体及下丘脑Ⅱ型脱碘酶泛素化修饰在慢性碘过量致TSH升高中的作用及机制研究

项目编号： No.81670719

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 姜雅秋

作者单位： 中国医科大学

项目金额： 25万元

中文摘要： 流行病学调查发现TSH水平随碘摄入量的增加而升高，但是机制尚不明确。Ⅱ型脱碘酶（D2）在下丘脑-垂体-甲状腺轴中起着至关重要的作用，其活性的变化会导致TSH的改变。本课题组前期动物实验发现：慢性碘过量大鼠模型中TSH升高，垂体D2活性下降。在此基础上，本课题组将进一步探究慢性碘过量导致D2活性降低的原因。我们提出假说：慢性碘过量使D2泛素-蛋白酶体通路的关键酶变化→垂体/下丘脑中D2脱碘酶的泛素化增强→D2活性减弱→T4向T3的转化率下降、T3减少→对TSH/TRH的抑制作用减弱→TSH升高。本课题组利用已建立的慢性碘过量大鼠模型，采用免疫共沉淀，双分子荧光等实验方法探究慢性碘过量对D2泛素化通路的影响，同时在体外细胞实验中予以碘和T4干预，进一步探讨碘在D2的泛素化中的作用机制。通过从整体、组织、细胞和分子不同层面探讨慢性碘过量致TSH升高的机制，为制定合理安全的碘摄入量提供科学依据。

中文关键词： Ⅱ型脱碘酶；碘；促甲状腺激素；泛素化

英文摘要： Epidemiological investigation indicated that prolonged high iodine intake would lead to elevation of serum TSH level, but the mechanism is elusive. Type 2 iodothyronine deiodinase(D2) plays a crucial role in hypothalamic-pituitary-thyroid axis, and its varying of activity could lead to changing of TSH. Our previous animal experiments have proved that activity of D2 is surpressed and TSH level increases in Wistar rats fed with long-term high iodine. Based on these data, we further explore the case of that long-term high iodine lead to activity of D2 surpressed. We hypothesis that chronic iodine overdose would change key enzyme of D2 ubiquitin-proteasome pathway→increase ubiqutination of D2 in pituitary/hypothalamus→activity of D2 decreases→conversion rate of T4 to T3 decreases and T3 decreases→the supression effect on TSH/TRH decreases→TSH increases. Our study aims to eluminate the effect of iodine on D2 ubiquitination after we had sucessfully built the iodine induced TSH elevation rat model and its potential mechanism acording to co-immunoprecipitation, immunofluorescence and so on, besides, some in vitro expriments would be processed in order to further clarify its mechamism. Acording to the different levers of body, tissue, cell and molecule, we would explore the mechanism that iodine induces TSH elevation, providing theoretical basis for the iodine suppliment policy making.

英文关键词： type 2 iodothyronine deiodinase; iodine;Thyroid stimulating hormone;ubiquitination