The Role of Energy Balance in Gonadotrope and Reproductive Function

能量平衡在促性腺激素和生殖功能中的作用

• 批准号: 10731507
• 负责人: Dequina Angelina Nicholas
• 金额: $ 8.16万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10731507
• 关键词: Ablation; Anabolic steroids; Androgen Receptor; Androgens; B-Lymphocytes; Bioinformatics; Cell Line; Cells; Chronic; Complex; Data; Etiology; Female; Fertility; Fertility Disorders; Functional disorder; Future; GNRH1 gene; Glucose; Glycolysis; Goals; Gonadotropins; Hormone secretion; Human; Immune; Immunologic Stimulation; Immunology; Immunophenotyping; In Vitro; Inflammation; Inflammatory; Knock-out; Knockout Mice; Knowledge; Luteinizing Hormone; Measures; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mus; Myeloid Cells; Neurosecretory Systems; Nonesterified Fatty Acids; Nutrient availability; Oxidative Phosphorylation; Pathologic; Pathway interactions; Phase; Phenotype; Pituitary Gland; Polycystic Ovary Syndrome; Process; Production; RNA; Reproduction; Reproductive Endocrinology; Reproductive Physiology; Research; Respiration; Role; SLC2A1 gene; Surface; Symptoms; Syndrome; System; Testing; Testosterone; Training; Transgenic Mice; Translating; Translational Regulation; Translations; Validation; Woman; Work; aged; anaerobic glycolysis; blood glucose regulation; career; comorbidity; conditional knockout; cytokine; deprivation; energy balance; female fertility; fertility improvement; glucose metabolism; glucose uptake; improved; in vivo; inhibitor; knock-down; mouse model; novel; overexpression; programs; reproductive; reproductive function; reproductive system disorder; response; skills; therapeutic target; transcriptome; treatment strategy

PROJECT SUMMARY Polycystic Ovary Syndrome (PCOS) is the most common fertility disorder in reproductive-aged women. Women with PCOS have elevated gonadotropin luteinizing hormone (LH), androgens, glucose, free fatty acids (FFAs), and inflammatory cytokines. Concomitant increases in LH and testosterone in both women with PCOS and mouse models of PCOS counter the well-established paradigm that testosterone suppresses the neuroendocrine axis. Mechanisms behind this paradox are largely unexplored. LH translation and secretion are innately energy- dependent processes. Therefore, gonadotrope cellular metabolism may explain the counterintuitive relationship between androgens (anabolic steroids) and LH in PCOS. The overall goal of this proposal is to investigate the impact of gonadotrope glucose metabolism on LH secretion and fertility in both normal and PCOS-like conditions. The overarching hypothesis of this proposal is cellular metabolism in gonadotropes regulates LH synthesis; and factors associated with PCOS, including glucose, androgens, and inflammatory cytokines, perturb gonadotrope energy balance and therefore LH secretion. In Aim 1, we will define the metabolic program required for normal gonadotrope function. We hypothesize that gonadotropes utilize glucose to support LH production and secretion. We will test the impact of glucose deprivation on GnRH challenge in vitro and in vivo. In vitro, we will perform comprehensive analysis of gonadotrope glycolysis and oxidative phosphorylation as they relate to nutrient availability and LH secretion. In vivo, we will test the effects of gonadotrope specific glucose transporter 1 (GLUT1) knock out on female fertility. In Aim 2, we will decipher how androgens increase gonadotrope glucose metabolism. We hypothesize that androgens increase gonadotrope utilization of glucose to drive LH secretion by translational regulation of GLUT1. We will assess the impact of androgen on glucose uptake after silencing GLUT1 in cell lines and use gonadotrope specific GLUT1 or androgen receptor KO mice to determine the role of gonadotrope GLUT1 in PCOS. In Aim 3, we will elucidate the contribution of PCOS-induced inflammation to gonadotrope metabolism and function. We hypothesize that chronic inflammation directly modulates gonadotrope LH secretion and contributes to reproductive dysfunction in PCOS. Using complex bioinformatic approaches, we will identify the immunophenotype specific to PCOS and assess the contribution of immune cells to PCOS etiology using immune deficient transgenic mouse models. Together, these Aims will 1) outline a role for gonadotrope energy balance in PCOS, 2) explain how androgens increase LH, and 3) identify specific inflammatory pathways as potential therapeutic targets in PCOS. In the K99 mentored phase, Dr. Nicholas will be trained in reproductive physiology and a PCOS mouse model that was established by her mentors. These new skills will be combined with her previous expertise in immunology to launch a successful career dissecting the role of inflammation in reproductive and metabolic disease.

项目摘要 多囊卵巢综合征（PCOS）是育龄妇女最常见的生育障碍。妇女 PCOS患者促性腺激素促黄体生成激素（LH）、雄激素、葡萄糖、游离脂肪酸（FFA） 和炎性细胞因子。患有多囊卵巢综合症和多囊卵巢综合症的女性的LH和睾酮同时增加 PCOS的小鼠模型与睾酮抑制神经内分泌的公认范式相反， 轴线这一悖论背后的机制在很大程度上尚未探索。LH翻译和分泌是天生的能量- 依赖过程。因此，促性腺激素细胞代谢可以解释这种违反直觉的关系 雄激素（合成代谢类固醇）和LH在PCOS中的作用。本提案的总体目标是调查 促性腺激素葡萄糖代谢对正常和PCOS样状态下LH分泌和生育力影响 该提议的首要假设是促性腺激素细胞代谢调节LH合成; 与PCOS相关的因素，包括葡萄糖、雄激素和炎性细胞因子，干扰促性腺激素 能量平衡和LH分泌。在目标1中，我们将定义正常代谢所需的代谢程序。 促性腺激素功能。我们假设促性腺激素利用葡萄糖来支持LH的产生和分泌。 我们将在体外和体内测试葡萄糖剥夺对GnRH激发的影响。在体外，我们将执行 促性腺激素糖酵解和氧化磷酸化与营养素关系的综合分析 可用性和LH分泌。在体内，我们将测试促性腺激素特异性葡萄糖转运蛋白1的作用， （GLUT 1）敲除对女性生育力的影响。在目标2中，我们将解释雄激素如何增加促性腺激素葡萄糖 新陈代谢.我们假设雄激素增加促性腺激素对葡萄糖的利用以驱动LH分泌 通过GLUT 1的翻译调节。我们将评估雄激素沉默后对葡萄糖摄取的影响。 GLUT 1在细胞系中的作用，并使用促性腺激素特异性GLUT 1或雄激素受体KO小鼠来确定 促性腺激素GLUT 1在PCOS中的作用在目标3中，我们将阐明PCOS诱导的炎症对 促性腺激素代谢和功能。我们假设慢性炎症直接调节 促性腺激素LH分泌，并导致PCOS的生殖功能障碍。使用复杂的生物信息学 方法，我们将确定PCOS的免疫表型，并评估免疫细胞的贡献 使用免疫缺陷转基因小鼠模型研究PCOS病因。总之，这些目标将1）概述一个角色 对于PCOS的促性腺激素能量平衡，2）解释雄激素如何增加LH，3）确定特定的 炎症通路作为PCOS的潜在治疗靶点。在K99辅导阶段，尼古拉斯博士将 接受生殖生理学培训和由导师建立的PCOS小鼠模型。这些 新的技能将与她以前在免疫学方面的专业知识相结合，以开展成功的职业解剖 炎症在生殖和代谢疾病中的作用。