Sex Steroids, Kisspeptin and Regulation of GnRH

性类固醇、Kisspeptin 和 GnRH 的调节

• 批准号: 8451336
• 负责人: GLORIA E HOFFMAN
• 金额: $ 41.95万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-30 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451336
• 关键词: Adult; Androgens; Attenuated; Cell Line; Cell membrane; Cells; Competence; Estradiol; Estrogens; Feedback; G Protein-Coupled Receptor 54; Gene Expression; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Hypothalamic structure; In Vitro; KISS1R gene; Knockout Mice; Ligands; Mammals; Mediating; Messenger RNA; Microdialysis; Monitor; Mus; Neurohormones; Neurons; Neurosecretion; Neurosecretory Systems; Outcome; Pattern; Peptides; Physiological; Polycystic Ovary Syndrome; Population; Preoptic Areas; Refractory; Regulation; Resistance; Role; Signal Transduction; Structure of nucleus infundibularis hypothalami; Synapses; System; Testing; Time; Wild Type Mouse; kisspeptin; mutant; prenatal; programs; reproductive axis; reproductive development; response

DESCRIPTION (provided by applicant): The release of LH is under regulation by the neurohormone gonadotropin releasing hormone (GnRH). Recently, the peptide kisspeptin (KP) which signals through a G-protein coupled receptor, GPR54, was found to be a key component in the regulation of GnRH. Evidence for a direct role for KP at the level of the GnRH neuron comes from anatomical and in vitro studies in GnRH expressing cell lines. Two principal populations of KP neurons are described in the hypothalamus: one in the arcuate nucleus (AN) and one in a region of the preoptic area, the AVPV. The AVPV KP neurons project directly to GnRH neurons and stimulate GnRH neurons at the time of the estrogen induced LH surge, while the AN population is implicated in negative feedback. This proposal will explore the role of estrogen in the neuroendocrine regulation of the gonadotropin surge in three aims. Aim 1 will determine if the negative and positive feedback actions of estradiol (E2) are mediated by activation of ERa in KP neurons. The responses of KP cell-specific ERa knockout (KERaKO) mice to treatments that evoke negative and positive feedback actions on LH neurosecretion will be assessed using a newly developed microdialysis system. Aim 2 will determine if prenatal androgen exposure (PNA), which induces features of polycystic ovary disease, programs resistance to E2 feedback actions in KP neurons. KP cell-specific AR null mutant (KARKO) mice will be generated and proposed studies will determine if they are refractory to androgenic programming of altered negative and positive feedback actions of E2. Aim 3 will determine the role of E2 in modulating KP GPR54 signaling in the regulation of the GnRH neuron. To determine if GPR54 activation in GnRH neurons mediates the physiological regulation of GnRH expression by KP neurons, the responsiveness of GnRH neuron-specific GPR54 knockout (GnRH-GPR54KO) mice to E2 negative and positive feedback actions will be assessed. The role of ER¿ in mediating E2 negative feedback and KP mediated synthesis and secretion of GnRH will be determined. Overall, these studies will provide a systematic, hierarchical assessment of the effects of E2 in the neuroendocrine control of the gonadotropin surge, and determine the mechanisms by which early androgen exposure may program resistance to E2 feedback actions.

描述（申请人提供）：黄体生成素的释放受神经激素促性腺激素释放激素（GnRH）的调节。最近，通过g蛋白偶联受体GPR54发出信号的肽kisspeptin （KP）被发现是调节GnRH的关键成分。KP在GnRH神经元水平上的直接作用的证据来自于对表达GnRH的细胞系的解剖和体外研究。在下丘脑中描述了两个主要的KP神经元群：一个在弓状核（AN）中，另一个在视前区（AVPV）中。AVPV KP神经元直接投射到GnRH神经元，并在雌激素诱导的LH激增时刺激GnRH神经元，而AN群体则涉及负反馈。本课题将从三个方面探讨雌激素在神经内分泌调节促性腺激素激增中的作用。目的1将确定雌二醇（E2）的负反馈和正反馈作用是否由KP神经元中ERa的激活介导。KP细胞特异性ERa敲除（KERaKO）小鼠对LH神经分泌的负反馈和正反馈作用的反应将使用新开发的微透析系统进行评估。目的2将确定是否产前雄激素暴露（PNA），诱导多囊卵巢疾病的特征，程序抵抗E2反馈作用的KP神经元。将产生KP细胞特异性AR零突变（KARKO）小鼠，并提出研究将确定它们是否对E2改变的负反馈和正反馈作用的雄激素编程具有耐受性。目的3将确定E2在调节GnRH神经元中调节KP GPR54信号的作用。为了确定GPR54在GnRH神经元中的激活是否介导了KP神经元对GnRH表达的生理调节，我们将评估GnRH神经元特异性GPR54敲除（GnRH- gpr54ko）小鼠对E2负反馈和正反馈行为的反应性。将确定ER¿在介导E2负反馈和KP介导的GnRH合成和分泌中的作用。总的来说，这些研究将提供一个系统的、分层的评估E2在神经内分泌控制促性腺激素激增中的作用，并确定早期雄激素暴露可能对E2反馈作用产生耐药性的机制。