Integration of NKB and Kisspeptin Control of GNRH Secret

项目二（Kl：研讨会） 在过去的五年里，项目II探索了kisspeptin作为GnRH强有力刺激物的生理学 分泌物项目II在当前资助周期的重点是将kisspeptin与另一种药物结合， 最近被认为与GnRH缺乏症的遗传学有关的神经肽，神经激肽B。患者 在神经激肽通路中有突变的人，其促性腺功能减退的逆转率很高， 恢复内源性GnRH诱导的LH脉冲。第一个具体的目的是探讨亚表型的 在Kisspeptin和神经激肽B通路突变的患者中， 特别是逆转和性类固醇暴露之间的关系。第二个具体目标是探索 Kisspeptin和神经激肽B刺激正常人GnRH分泌生理相互作用 志愿者和患者携带突变的每一个这些信号通路。这些工具将包括 通过输注连续给予kisspeptin-（作为替代kisspeptin受体拮抗剂），和 一种神经激肽B受体拮抗剂。第三个具体目标扩展了人类使用的生理工具， 以及将神经激肽B内具有靶向缺失的小鼠的表型分型 途径，并开发可逆性促性腺激素减退症的小鼠模型。

PROJECT II (Kl: SEMINARA) Over the last five years, Project II has explored the physiology of kisspeptin as a powerful stimulus of GnRH secretion. The focus of Project II in the current grant cycle is the integration of kisspeptin with another neuropeptide that has recently been implicated in the genetics of GnRH deficiency, neurokinin B. Patients with mutations in the neurokinin pathway have high rates of reversal of their hypogonadotropism with restoration of endogenous GnRH-induced LH pulses. The first specific aim explores the subphenotype of reversible GnRH deficiency in patients with mutations in the kisspeptin and neurokinin B pathways, and in particular, the relationship between reversal and sex steroid exposure. The second specific aim explores the physiologic interplay between kisspeptin and neurokinin B in stimulating GnRH secretion in normal volunteers and patients carrying mutations in each of these signaling pathways. These tools will include continuous kisspeptin administration via infusion-(acting as a surrogate kisspeptin receptor antagonist), and a neurokinin B receptor antagonist. The third specific aim extends the physiologic tools used in the human into the mouse, as well as incorporating phenotyping of mice with targeted deletions within the neurokinin B pathway, and developing a mouse model of reversible hypogonadotropism.