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

基本信息

批准号：
9892573
负责人：
Dequina Angelina Nicholas
金额：
$ 10.71万
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：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892573
关键词：
Address Anabolic steroids Androgen Receptor Androgens B-Lymphocytes Bioinformatics Cell Line Cells Chronic Comorbidity Complex Data Etiology Female Fertility Fertility Disorders Functional disorder Future GNRH1 gene Glucose Glycolysis Goals Gonadotrope Cell Gonadotropins Hormone secretion Human Immune 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 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 cytokine deprivation energy balance female fertility fertility improvement glucose metabolism glucose uptake improved in vivo inhibitor/antagonist knock-down mouse model novel overexpression programs reproductive reproductive function response skills therapeutic target transcriptome treatment strategy

项目摘要

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.

项目概要多囊卵巢综合症（PCOS）是育龄妇女最常见的生育障碍。女性多囊卵巢综合症患者的促性腺激素、黄体生成素 (LH)、雄激素、葡萄糖、游离脂肪酸 (FFA) 升高，和炎症细胞因子。患有 PCOS 和 PCOS 小鼠模型与睾酮抑制神经内分泌的既定范式相反轴。这一悖论背后的机制很大程度上尚未被探索。 LH 翻译和分泌是天生的能量- 依赖进程。因此，促性腺激素细胞代谢可以解释这种违反直觉的关系 PCOS 患者中雄激素（合成代谢类固醇）和 LH 之间的关系。该提案的总体目标是调查在正常和 PCOS 样条件下，促性腺激素葡萄糖代谢对 LH 分泌和生育力的影响。该提案的总体假设是促性腺激素的细胞代谢调节 LH 合成；和与 PCOS 相关的因素，包括葡萄糖、雄激素、炎症细胞因子、扰乱促性腺激素能量平衡以及 LH 分泌。在目标 1 中，我们将定义正常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 挑战的影响。在体外，我们将进行促性腺激素糖酵解和氧化磷酸化与营养相关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 (GLUT1) 降低女性生育能力。在目标 2 中，我们将解读雄激素如何增加促性腺激素葡萄糖代谢。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 GLUT1 的翻译调节。我们将评估沉默后雄激素对葡萄糖摄取的影响 GLUT1在细胞系中的作用并用促性腺激素特异性GLUT1或雄激素受体KO小鼠来确定作用 PCOS 中促性腺激素 GLUT1 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的代谢和功能。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 特有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。这些目标共同将 1) 概述一个角色对于 PCOS 中的促性腺激素能量平衡，2) 解释雄激素如何增加 LH，以及 3) 确定具体的炎症通路作为 PCOS 的潜在治疗靶点。在K99指导阶段，尼古拉斯博士将接受生殖生理学培训和导师建立的多囊卵巢综合症小鼠模型。这些新技能将与她之前在免疫学方面的专业知识相结合，开启成功的解剖职业生涯炎症在生殖和代谢疾病中的作用。