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Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway

脑干-下丘脑神经通路对营养不良期间促性腺激素分泌的调节

基本信息

批准号：
10684307
负责人：
KELLIE Breen Church
金额：
$ 52.77万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684307
关键词：
Ablation Acute Amenorrhea Anatomy Animal Model Antimetabolites Brain Stem Catecholamines Cells Chronic Corticotropin-Releasing Hormone Receptors Coupling Data Deoxyglucose Development Disease Equilibrium Estradiol Estrus FOS gene Female Fertility Foundations Functional disorder GNRH1 gene Generations Genetic Glucose Goals Gonadotropin Hormone Releasing Hormone Gonadotropins Hormone secretion Hypothalamic structure Impairment Infertility KISS1 gene Knock-out Luteinizing Hormone Malnutrition Mediating Mediator Menstruation Disturbances Metabolic Metabolic Control Metabolic stress Methods Molecular Mus Neural Pathways Neurons Neuropeptides Neurosecretory Systems Norepinephrine Ovarian Ovarian Cycles Pathway interactions Periodicity Physiologic pulse Physiological Population Process Production Regulation Reproduction Research Research Personnel Role Signal Transduction Stress Talents Testing Transgenic Mice Transgenic Organisms Ventricular Woman Work anovulatory disorder antagonist biological adaptation to stress designer receptors exclusively activated by designer drugs energy balance functional hypothalamic amenorrhea knock-down knowledge integration neural neuromechanism neurotransmission novel paraventricular nucleus pharmacologic prevent receptor reproductive reproductive function response tool urocortin

项目摘要

PROJECT SUMMARY/ABSTRACT The overall goal of this research is to understand how stress disrupts the ovarian cycle. Chronic undernutrition is a type of metabolic stress that impairs reproduction across species, and in women is implicated in the development of functional hypothalamic amenorrhea, an anovulatory disorder resulting from inadequate gonadotropin secretion. Although the tight coupling of energy balance to reproductive capacity is recognized in principle, the neuroendocrine loci and molecular mechanisms that mediate ovarian cycle dysfunction during undernutrition remain poorly understood. In females, ovulatory cyclicity is dependent on two populations of kisspeptin (Kiss1) neurons within the hypothalamus that coordinate gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) pulses and generation of the preovulatory GnRH/LH surge. Disruption of either arcuate Kiss1 (ARCKiss1) control of LH pulses or anteroventral periventricular Kiss1 (AVPVKiss1) control of the LH surge would be anticipated to impair ovarian cyclicity in females. Our preliminary studies demonstrate that chronic undernutrition rapidly disrupts ovarian cyclicity in female mice via impairment of both pulsatile LH secretion and the LH surge. We show that these inhibitory effects on the ovarian cycle are recapitulated by activation of brainstem A2NE neurons or via central administration of urocortin 2 (UCN2), a neuropeptide that specifically activates corticotropin-releasing hormone receptor 2 (CRHR2). Our observations that antagonism of CRHR2 or knockdown of CRHR2 in Kiss1 cells diminishes reproductive suppression in response to undernutrition or A2NE activation provide the foundation to test this neural pathway mediating the effects of undernutrition on reproductive neuroendocrine function. Currently it is not known how undernutrition disrupts the cycle or the neural processes controlling pulsatile or surge LH secretion. We propose to fill this gap by testing the overall hypothesis: Chronic undernutrition disrupts the ovarian cycle and fertility via activation of a NE – UCN2 – Kiss1 neural pathway that impairs two modes of LH secretion: LH pulses and the preovulatory LH surge. Aim1 will utilize a genetic knockout approach to investigate the role of CRHR2 within Kiss1 cells as a mediator of disrupted cycles, LH pulses, and the LH surge during chronic undernutrition. Aim 2.1 will utilize a chemogenic approach to test the sufficiency of this brainstem population to impair the ovarian cycle, inhibit AVPVKiss1 control of the LH surge, and disrupt ARCKiss1 control of LH pulses. Aim 2.2 will determine the necessity of A2NE signaling for disrupted ovarian cyclicity and impaired neural pathways underlying pulsatile and surge LH secretion. This project will employ powerful physiological, anatomical, molecular and transgenic tools to advance our knowledge of integrated stress responses and the regulation of gonadotropin secretion. Results from this proposal will provide enhanced understanding of the metabolic control of reproduction that may influence the management and treatment for anovulatory disorders resulting from negative energy balance. All necessary animal models and methods are in place to complete these studies.

项目概要/摘要这项研究的总体目标是了解压力如何扰乱卵巢周期。慢性营养不良是一种代谢应激，会损害跨物种的繁殖，并且在女性中与功能性下丘脑性闭经的发展，这是一种由于功能不足而导致的无排卵障碍促性腺激素分泌。尽管人们认识到能量平衡与生殖能力的紧密联系介导卵巢周期功能障碍的原理、神经内分泌位点和分子机制营养不良期间的情况仍然知之甚少。对于女性来说，排卵周期取决于两个因素下丘脑内协调促性腺激素释放的 Kisspeptin (Kiss1) 神经元群激素 (GnRH) 和黄体生成素 (LH) 脉冲以及排卵前 GnRH/LH 激增的产生。 LH 脉冲的弓形 Kiss1 (ARCKiss1) 控制或前腹侧脑室周围 Kiss1 的破坏 (AVPVKiss1) LH 激增的控制预计会损害女性的卵巢周期。我们的初步研究表明，慢性营养不良通过以下途径迅速破坏雌性小鼠的卵巢周期：搏动性 LH 分泌和 LH 激增均受到损害。我们证明这些抑制作用通过脑干 A2NE 神经元的激活或通过中央给予尿皮质素来重现卵巢周期 2 (UCN2)，一种特异性激活促肾上腺皮质激素释放激素受体 2 (CRHR2) 的神经肽。我们的观察到 Kiss1 细胞中 CRHR2 的拮抗或 CRHR2 的敲低会降低生殖能力对营养不良或 A2NE 激活的抑制为测试该神经通路提供了基础介导营养不良对生殖神经内分泌功能的影响。目前尚不清楚如何营养不良会破坏控制脉动或激增 LH 分泌的循环或神经过程。我们建议通过测试总体假设来填补这一空白：慢性营养不良会破坏卵巢周期和生育能力通过激活 NE – UCN2 – Kiss1 神经通路，损害两种 LH 分泌模式：LH 脉冲和排卵前 LH 激增。 Aim1 将利用基因敲除方法来研究 CRHR2 的作用 Kiss1 细胞内作为慢性营养不良期间周期中断、LH 脉冲和 LH 激增的介质。目标 2.1 将利用化学方法来测试脑干群是否足以损害卵巢周期，抑制 AVPVKiss1 对 LH 浪涌的控制，并破坏 ARCKiss1 对 LH 脉冲的控制。目标 2.2 将确定 A2NE 信号传导对于卵巢周期紊乱和搏动性神经通路受损的必要性和 LH 分泌激增。该项目将采用强大的生理、解剖、分子和转基因技术提高我们对综合应激反应和促性腺激素分泌调节的了解的工具。该提案的结果将加深对生殖代谢控制的理解，这可能影响负能量平衡引起的无排卵障碍的管理和治疗。全部完成这些研究所需的动物模型和方法已经到位。