甲状腺ホルモンによる生殖制御におけるＧｎＩＨシステムの作用機構

GnIH系统在甲状腺激素生殖控制中的作用机制

基本信息

批准号：
15F15909
负责人：
筒井和義
金额：
$ 1.47万
依托单位：
Waseda University
依托单位国家：
日本
项目类别：
Grant-in-Aid for JSPS Fellows
财政年份：
2015
资助国家：
日本
起止时间：
2015-04-24 至 2017-03-31
项目状态：
已结题

项目摘要

Thyroid disorders lead to abnormal pubertal development. Although interactions between the thyroid and reproductive endocrine systems are suggested, the detailed mechanisms of how thyroid hormone influences pubertal onset remain unclear. The hypothalamic peptide, gonadotropin-inhibitory hormone (GnIH) was shown to be decreased in the early prepubertal stage, suggesting the possible role of GnIH on pubertal onset. Therefore, we investigated the involvement of GnIH in thyroid status-induced pubertal disorders.To do this, we induced hypothyroidism and hyperthyroidism in juvenile female mice, then analyzed the change in the regulatory factors of the reproductive axis. Hypothyroidism showed delayed pubertal onset with increased GnIH expression, however hypothyroidism-induced delayed puberty was prevented by GnIH-knockout, suggesting that GnIH may mediate the effect of hypothyroidism on pubertal delay. Reversely, hyperthyroidism had no effect on pubertal onset, however GnIH expression was significantly decreased, indicating the negative correlation between thyroid status and GnIH expression. Further, we found that hypothalamic GnIH neurons express thyroid hormone receptors (TRs), which may convey thyroid hormone signals directly to GnIH neurons. Although TRs did not directly bind to GnIH promoter region, thyroid status actively altered the chromatin modifications in GnIH promoter region.Our findings indicate a novel function of GnIH to mediate the cross-talk between the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-gonadal axes in proper pubertal development.

甲状腺疾病导致异常的青春期发展。尽管提出了甲状腺和生殖内分泌系统之间的相互作用，但甲状腺激素如何影响青春期发作的详细机制尚不清楚。下丘脑肽，促性腺激素抑制性激素（GNIH）在早期前伯伯碱阶段被证明降低，这表明GNIH可能在青春期发作中起作用。因此，我们研究了GNIH参与甲状腺状态引起的青春期疾病。要做到这一点，我们诱导了少年雌性小鼠的甲状腺功能减退症和甲状腺功能亢进症，然后分析了生殖轴的调节因素的变化。甲状腺功能减退症显示出延迟的青春期发作，GNIH表达增加，但是甲状腺功能减退症引起的延迟青春期是通过GNIH敲除的，这表明GNIH可能介导甲状腺功能减退症对青春期延迟的影响。相反，甲状腺功能亢进对青春期没有影响，但是GNIH表达显着降低，表明甲状腺状态与GNIH表达之间的负相关性。此外，我们发现下丘脑GNIH神经元表达甲状腺激素受体（TRS），可以将甲状腺激素信号直接传达给GNIH神经元。尽管TRS没有直接与GNIH启动子区域结合，但甲状腺状态积极改变了GNIH启动子区域中的染色质修饰。我们的发现表明GNIH的新功能介导了下丘脑 - 甲状腺甲状腺 - 甲状腺功能低下和甲状腺素 - 刺激性 - 钉叶核轴轴的串扰。