GONADOTROPIN-RELEASING HORMONE ACTION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这些都是高度转化的研究，我们观察到突变性疾病的潜在基础通常是其他功能蛋白的错误路由，在这种情况下是促性腺激素 释放激素（GnRH）受体（R）-但其他人现在已经证实了其他受体，离子通道和酶。我们已经证明，这些突变受体可以被药物分子伴侣拯救并恢复功能。我们已经确定，路由的调节也是一种正常类型的翻译后调节，发生在常规细胞功能，可以控制。在前一阶段，我们已经表明，错误折叠的人（h）GnRHR可以重新折叠，因此治疗药物不需要持续存在。我们还表明，hGnRHR的控制有助于解释这种受体对振幅和频率调制信号的反应能力。对GnRHR类似物进行了潜在治疗作用的筛选，并发表了一篇综述，建立了药理作用的分子机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. These are highly translational studies in which we have observed that the underlying basis of mutational disease is frequently the mis-routing of otherwise functional proteins, in this case the gonadotropin releasing hormone (GnRH) receptor (R)-but others have now confirmed this for additional receptors, ion channels and enzymes. We have shown that these mutant receptors can be rescued and restored to function by pharmacological chaperones. We have determined that the regulation of routing is also a normal type of post-translational regulation that occurs in routine cell function and can be controlled. During the prior period we have shown that misfolded human (h) GnRHR can be refolded so that therapeutic agents need not be continuously present. We have also shown that control of hGnRHR helps explain the ability of this receptor to respond to both amplitude and frequency modulated signals. GnRHR analogs were screened for potential therapeutic action and a review was published and the molecular mechanism of pharmacoperone action was established.