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首页> 外文期刊>American Journal of Physiology >Reproductive physiology of a humanized GnRH receptor mouse model: application in evaluation of human-specific analogs.
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Reproductive physiology of a humanized GnRH receptor mouse model: application in evaluation of human-specific analogs.

机译：人源化GnRH受体小鼠模型的生殖生理学：在评估人类特异性类似物中的应用。

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摘要

The human GnRH receptor (GNRHR1) has a specific set of properties with physiological and pharmacological influences not appropriately modeled in laboratory animals or cell-based systems. To address this deficiency, we have generated human GNRHR1 knock-in mice and described their reproductive phenotype. Measurement of pituitary GNRHR1 transcripts from homozygous human GNRHR1 knock-in (ki/ki) mice revealed a severe reduction (7- to 8-fold) compared with the mouse Gnrhrl in wild-type mice. ~(125)I-GnRH binding assays on pituitary membrane fractions corroborated reduced human GNRHR1 protein expression in ki/ki mice, as occurs with transfection of human GNRHR1 in cell lines. Female homozygous knock-in mice displayed normal pubertal onset, indicating that a large reduction in GNRHR1 expression is sufficient for this process. However, ki/ki females exhibited periods of prolonged estrous and/or metestrous and reduced fertility. No impairment was found in reproductive maturity or adult fertility in male ki/ki mice. Interestingly, the serum LH response to GnRH challenge was reduced in both knock-in males and females, indicating a reduced GNRHR1 signaling capacity. Small molecules targeting human GPCRs usually have poor activities at homologous rodent receptors, thus limiting their use in preclinical development. Therefore, we tested a human-specific GnRHl antagonist, NBI-42902, in our mouse model and demonstrated abrogation of a GnRH1-induced serum LH rise in ki/ki mice and an absence of effect in littermates expressing the wild-type murine receptor. This novel model provides the opportunity to study the human receptor in vivo and for screening the activity of human-specific GnRH analogs.
机译：人GnRH受体（GNRHR1）具有一组特定的特性，在实验室动物或基于细胞的系统中未适当建模，具有生理和药理学影响。为了解决这一缺陷，我们已经产生了人类GNRHR1敲入小鼠并描述了它们的生殖表型。测量纯合的人GNRHR1敲入（ki / ki）小鼠的垂体GNRHR1转录本，与野生型小鼠中的Gnrhrl相比，严重降低（7至8倍）。垂体膜级分的〜（125）I-GnRH结合测定证实了Ki / ki小鼠中人GNRHR1蛋白表达的降低，就像在细胞系中转染人GNRHR1一样。雌性纯合敲入小鼠表现出正常的青春期发作，表明GNRHR1表达的大量减少足以完成该过程。但是，ki / ki雌性动物发情和/或发情期延长，生育能力降低。在雄性ki / ki小鼠中，未发现生殖成熟度或成年能力受损。有趣的是，在敲入的雄性和雌性中，血清对GnRH激发的LH反应均降低，表明GNRHR1信号传导能力降低。靶向人GPCR的小分子通常对同源啮齿动物受体的活性较弱，因此限制了它们在临床前开发中的使用。因此，我们在我们的小鼠模型中测试了人类特异性GnRH1拮抗剂NBI-42902，并证实了ki / ki小鼠中GnRH1诱导的血清LH升高的废除，并且在表达野生型鼠受体的同窝幼仔中没有作用。这种新颖的模型提供了在体内研究人类受体并筛选人类特异性GnRH类似物活性的机会。

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