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Sex Steroids, Kisspeptin and Regulation of GnRH

性类固醇、Kisspeptin 和 GnRH 的调节

基本信息

批准号：
10613337
负责人：
Jon E Levine
金额：
$ 46.52万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613337
关键词：
Acceleration Adult Adult Children Alleles Animal Model Animals Axon Blood Vessels Brain Breeding Cell Nucleus Cells Central Nervous System Defect Delayed Puberty Development Doxycycline Dynorphins ESR1 gene ESR2 gene Elements Enterobacteria phage P1 Cre recombinase Estradiol Estrogen Receptor alpha Feedback Female Fertility Fertility Disorders Follicle Stimulating Hormone GNRH1 gene Gene Deletion Generations Genetic Genetic Recombination Gonadal Steroid Hormones Gonadotropin Hormone Releasing Hormone Gonadotropins Hormone secretion Hypothalamic structure Impairment Infertility Internal Ribosome Entry Site Intervention KISS1 gene Knock-out Laboratories Luteinizing Hormone Mediating Methodology Modeling Mus Neurokinin B Neurons Neuropeptides Neurosecretion Neurosecretory Systems Optics Partner in relationship Pattern Peptides Periodicity Phenotype Physiologic pulse Play Polycystic Ovary Syndrome Population Precocious Puberty Process Puberty Regulation Role Steroid Receptors Steroids Structure of nucleus infundibularis hypothalami Synapses System TACR3 gene Testing Ventricular autocrine dynorphin receptor functional hypothalamic amenorrhea gonad function inducible Cre innovation kappa opioid receptors knockout gene male mature animal median eminence mouse model neuromechanism novel paracrine preoptic nucleus prodynorphin receptor receptor binding reproductive reproductive axis reproductive function reproductive system disorder tool

项目摘要

Project Summary The central nervous system regulates gonadotropin secretion through neurosecretion of gonadotropin- releasing hormone (GnRH). GnRH is synthesized in preoptic and periventricular neurons, transported via intertwined processes that distribute as axonal-vascular terminals in the median eminence and released into the hypothalamic-hypophysial portal vasculature. GnRH binds receptors on gonadotropes to stimulate secretion and synthesis of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Neurosecretion of GnRH is pulsatile and is obligatory for sustaining normal gonadotropin secretion and synthesis. Kisspeptin (KISS1) neurons are a major GnRH afferent network that activates GnRH neurons during puberty, maintains GnRH release during adulthood, and transduces negative and positive feedback actions of gonadal steroids. In our studies we will test the hypothesis that KISS1 neurons, specifically those in the arcuate nucleus (ARC) that co-express the peptides neurokinin B (NKB) and prodynorphin (PDyn) (KNDy neurons), function as a GnRH pulse generator (Aim 1), with NKB mediating synchronized activation of KNDy cells (Aim 2) and dynorphin terminating each pulse discharge (Aim 3). These studies are significant because they will provide information on the cellular circuitries that govern GnRH pulse generation, and thus will shed new light on the pathophysiologic mechanisms underlying neuroendocrine-based fertility disorders, such as absent, delayed, or precocious puberty, functional hypothalamic amenorrhea, or polycystic ovary syndrome, and in the longer term, point to new potential targets for intervention in these reproductive impairments. The proposed studies will use powerful genetic tools to dissect and characterize the functional components of the kisspeptin-GnRH pulse generating system. To define the key elements of the pulse generator, we will utilize innovative genetically modified mouse models, each enabling an analysis of the consequences of kisspeptin neuron-specific gene deletion. We will first study the role of the KNDy neuronal population using a Kiss1fl/fl mouse recently created in our laboratory. This mouse will be bred to a prodynorphin Cre (Pdyn-IRES- Cre21,2) mouse, hereafter Pdyn-Cre, to eliminate Kiss1 in KNDy neurons. We have also developed a novel mouse bearing a doxycycline-inducible kisspeptin-Cre allele (iKiss-Cre mouse) that will enable temporal control over the selective deletion of genes from Kiss1 neurons. Two other lines, a NKBfl/fl mouse (developed in our laboratory) and an Oprk1fl/fl mouse (Jackson labs) will be crossed to Kiss1-Cre or iKiss-Cre mice to generate mice that will allow us to analyze the effects of kisspeptin neuron-specific deletion of NKB and Oprk1 on GnRH- triggered LH pulses. We will also use the iKiss-Cre mouse to delete and study the roles of steroid receptors in kisspeptin neurons in the adult. This temporally controlled gene deletion will eliminate a longstanding technical limitation of conventional steroid receptor knockout models in which steroid regulation of the axis is confounded by steroid developmental and organizational effects in the axis.

项目摘要中枢神经系统通过促性腺激素的神经分泌调节促性腺激素的分泌- 促性腺激素释放激素（GnRH）。GnRH在视前和室周神经元中合成，通过交织的过程，分布在正中隆起的轴突血管终端和释放到下丘脑-垂体门静脉系统。GnRH结合促性腺激素受体刺激分泌，促黄体生成素（LH）和促卵泡激素（FSH）的合成。GnRH的神经分泌是搏动性的，并且是维持正常促性腺激素分泌和合成所必需的。 Kisspeptin（KISS 1）神经元是一个主要的GnRH传入网络，在促性腺激素分泌过程中激活GnRH神经元。青春期，维持GnRH释放在成年期，并转导负反馈和正反馈行动，性腺类固醇在我们的研究中，我们将检验KISS 1神经元，特别是弓状核中的神经元的假设共表达肽神经激肽B（NKB）和强啡肽原（PDyn）的核（ARC）（KNDy神经元），作为GnRH脉冲发生器（Aim 1），NKB介导KNDy细胞的同步激活（Aim 2）和强啡肽终止每个脉冲放电（目的3）。这些研究很重要，因为它们将提供关于控制GnRH脉冲产生的细胞电路的信息，因此将为GnRH的产生提供新的线索。基于神经内分泌的生育障碍的病理生理机制，如缺乏，延迟，或性早熟、功能性下丘脑性闭经或多囊卵巢综合征，从长远来看，指出了对这些生殖障碍进行干预的新的潜在目标。拟议的研究将使用强大的遗传工具来剖析和表征功能性 Kisspeptin-GnRH脉冲发生系统的组成部分。为了定义脉冲发生器的关键元件，我们将利用创新的转基因小鼠模型，每一个模型都能分析 kisspeptin神经元特异性基因缺失。我们将首先研究KNDy神经元群体的作用，使用 Kiss 1fl/fl小鼠最近在我们的实验室创建。该小鼠将被培育成前强啡肽Cre（Pdyn-IRES-1）。 Cre 21，2）小鼠，下文称为Pdyn-Cre，以消除KNDy神经元中的Kiss 1。我们还发明了一种携带能够进行时间控制的多西环素诱导型kisspeptin-Cre等位基因的小鼠（iKiss-Cre小鼠）而不是选择性地删除Kiss 1神经元的基因。另外两个品系，NKBfl/fl小鼠（在我们的实验室中开发），实验室）和Oprk 1 fl/fl小鼠（杰克逊实验室）与Kiss 1-Cre或iKiss-Cre小鼠杂交以产生小鼠，这将使我们能够分析kisspeptin神经元特异性缺失NKB和Oprk 1对GnRH的影响，触发LH脉冲。我们还将使用iKiss-Cre小鼠删除并研究类固醇受体在 kisspeptin神经元在成人。这种暂时控制的基因缺失将消除一种长期存在的技术缺陷。常规类固醇受体敲除模型的局限性，其中轴的类固醇调节被混淆类固醇的发育和组织效应。