Investigation of Anatomical and Functional Mechanisms Underlying the Suppression of Gonadotropin Secretion by Metabolic Stress

代谢应激抑制促性腺激素分泌的解剖学和功能机制研究

• 批准号: 10267661
• 负责人: Richard Bryan McCosh
• 金额: $ 3.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267661
• 关键词: Achievement; Acute; Amenorrhea; Anatomy; Area; Brain Stem; Cardiovascular Diseases; Cell Culture Techniques; Cell Line; Cell Nucleus; Cells; Chronic Disease; Corticotropin-Releasing Hormone; Coupled; Data; Development; Disease; Dopamine-beta-monooxygenase; Ensure; Estrogens; FOS gene; Frequencies; GNRH1 gene; GTP-Binding Protein alpha Subunits, Gs; Genetic; Goals; Gonadotropins; Hormone secretion; Human; Hypoglycemia; Hypothalamic structure; Immunohistochemistry; In Situ Hybridization; Infertility; Infusion procedures; Insulin; Investigation; KISS1 gene; Knowledge; Label; LoxP-flanked allele; Luteinizing Hormone; Measurement; Mediating; Mental Health; Messenger RNA; Metabolic stress; Methods; Mission; Modeling; Molecular; Monkeys; Mus; Neurokinin B; Neurons; Norepinephrine; Osteoporosis; Pathway interactions; Peptides; Periodicity; Pharmacology; Physiologic pulse; Population; Protein Isoforms; Publishing; Rabies virus; Rattus; Regulation; Research; Reverse Transcriptase Polymerase Chain Reaction; Sheep; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Structure; Structure of area postrema; Structure of nucleus infundibularis hypothalami; Synapses; Testing; Training; United States National Institutes of Health; Virus; Woman; Work; base; biological adaptation to stress; career; experimental study; functional hypothalamic amenorrhea; innovation; knock-down; neural circuit; neuromechanism; paraventricular nucleus; post-doctoral training; receptor; receptor expression; skills; small hairpin RNA; urocortin

PROJECT SUMMARY Stress is a leading cause of functional hypothalamic amenorrhea and infertility. Amenorrhea is associated with cardiovascular disease, osteoporosis, and mental health, therefore elucidation of the mechanisms by which stress suppresses gonadotropin secretion may provide new avenues to protect against chronic illnesses. Metabolic stress occurs in healthy people as well as in several disease states. Insulin-induced hypoglycemia (IIH) is a reliable, repeatable and quantifiable model of acute metabolic stress that suppresses pulsatile luteinizing hormone (LH) secretion; however, the mechanisms that mediate the suppression of LH are not known. This proposal will use genetic, pharmacologic and molecular approaches to test the hypothesis that urocortin 2 cells in the paraventricular nucleus (PVN) are innervated by brainstem norepinephrine neurons, and project onto and inhibit kisspeptin neurons in the arcuate nucleus to suppress pulsatile LH secretion in IIH. In Aim 1, we will determine if urocortin 2 cells in the PVN receive anatomical and functional input from brainstem norepinephrine neurons during IIH. In Aim 2, we will determine if kisspeptin cells receive anatomical and functional input from urocortin 2 neurons in the PVN during IIH. In Aim 3, we will characterize the effects of urocortin 2 on ARC kisspeptin neuron function in an immortalized hypothalamic kisspeptin-expressing cell line. This project will examine the form and function of a brainstem-PVN-arcuate nucleus neural circuit to inhibit pulsatile LH secretion during metabolic stress. These experiments will test an innovative hypothesis involving urocortin 2 signaling that will advance our knowledge of integrated stress responses, regulation of gonadotropin secretion, and provide the applicant training in critical skills that will be necessary for a successful career in academic research.

项目概要 压力是功能性下丘脑性闭经和不孕症的主要原因。闭经与以下因素有关 心血管疾病、骨质疏松症和心理健康，因此阐明其机制 压力抑制促性腺激素分泌可能提供预防慢性疾病的新途径。 健康人以及多种疾病状态下都会出现代谢应激。胰岛素引起的低血糖 (IIH) 是一种可靠、可重复且可量化的急性代谢应激模型，可抑制脉动 黄体生成素（LH）的分泌；然而，介导 LH 抑制的机制并不 已知。该提案将使用遗传、药理学和分子方法来检验以下假设： 室旁核 (PVN) 中的尿皮质素 2 细胞由脑干去甲肾上腺素神经元支配，并且 投射并抑制弓状核中的 Kisspeptin 神经元，以抑制 IIH 中的搏动性 LH 分泌。在 目标 1，我们将确定 PVN 中的尿皮质素 2 细胞是否接收来自脑干的解剖和功能输入 IIH 期间的去甲肾上腺素神经元。在目标 2 中，我们将确定 Kisspeptin 细胞是否接受解剖学和 IIH 期间 PVN 中尿皮质素 2 神经元的功能输入。在目标 3 中，我们将描述以下因素的影响： 尿皮质素 2 对永生化下丘脑 Kisspeptin 表达细胞系中 ARC Kisspeptin 神经元功能的影响。 该项目将检查脑干-PVN-弓状核神经回路的形式和功能，以抑制 代谢应激期间的脉动 LH 分泌。这些实验将检验一个创新假设，涉及 urocortin 2 信号传导将提高我们对综合应激反应、调节的认识 促性腺激素分泌，并为申请人提供必要的关键技能培训 学术研究事业取得成功。