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：
10622020
负责人：
Dequina Angelina Nicholas
金额：
$ 6.91万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10622020
关键词：
Address Anabolic steroids Androgen Receptor Androgens Bioinformatics Cell Line Cells Chronic Complex Data Etiology Exclusion Family Female Fertility Fertility Disorders Functional disorder Future Glucose Glucose Transporter Glycolysis Goals Gonadotropins Hormone secretion Human Immune Immunology Immunophenotyping In Vitro Inflammation Inflammatory Knock-out Knockout Mice Knowledge Luteinizing Hormone Measures Mediating Metabolic Metabolism Modeling Mus Neurosecretory Systems Pathologic Pathway interactions Phenotype Pituitary Gland Polycystic Ovary Syndrome Post-Translational Regulation Process Production RNA Reproduction Role SLC2A1 gene Serum Surface Symptoms Syndrome System Testing Testosterone Transgenic Mice Translating Translations Validation Woman Work aged blood glucose regulation comorbidity conditional knockout cytokine energy balance female fertility fertility improvement glucose metabolism glucose uptake improved in vivo inhibitor macrophage member mouse model novel programs reproductive reproductive function 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, 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 that factors associated with PCOS, including glucose, androgens, and inflammatory cytokines, perturb gonadotrope energy balance through GLUT1 and therefore alter LH synthesis. We have determined that glycolysis is the metabolic program required for normal gonadotrope function. Gonadotropes utilize glucose to support LH production and secretion through Glucose transporter 1 (GLUT1) at the exclusion of other members of the glucose transporter family. In Aim 1, we will determine the effects of gonadotrope specific glucose transporter 1 (GLUT1) knock out on female fertility in mice. Using this model, we will decipher how androgens increase gonadotrope glucose metabolism. We hypothesize that androgens increase gonadotrope utilization of glucose to drive LH secretion by pre- and post- 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 KO mice to determine the role of gonadotrope GLUT1 in PCOS. In Aim 2, 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 reproduction and PCOS, 2) explain how androgens increase LH, and 3) identify specific inflammatory pathways as potential therapeutic targets in PCOS.

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。女性患有 PCOS 的人促性腺激素、黄体生成素 (LH)、雄激素、葡萄糖和炎症水平升高细胞因子。患有 PCOS 的女性和 PCOS 小鼠模型的 LH 和睾酮水平同时增加与睾酮抑制神经内分泌轴的既定范式相反。机制这一悖论背后的原因很大程度上尚未被探索。 LH 翻译和分泌本质上依赖于能量流程。因此，促性腺激素细胞代谢可以解释两者之间违反直觉的关系。多囊卵巢综合征中的雄激素（合成代谢类固醇）和 LH。该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 样条件下 LH 分泌和生育力的影响。这该提案的总体假设是与 PCOS 相关的因素，包括葡萄糖、雄激素和炎症细胞因子，通过 GLUT1 扰乱促性腺激素能量平衡，从而改变 LH 合成。我们已经确定糖酵解是正常促性腺激素功能所需的代谢程序。促性腺激素利用葡萄糖通过葡萄糖转运蛋白 1 (GLUT1) 支持 LH 的产生和分泌排除葡萄糖转运蛋白家族的其他成员。在目标 1 中，我们将确定以下效果：促性腺激素特异性葡萄糖转运蛋白 1 (GLUT1) 敲除小鼠雌性生育能力。使用这个模型，我们将破译雄激素如何增加促性腺激素葡萄糖代谢。我们假设雄激素通过翻译前和翻译后调节增加促性腺激素对葡萄糖的利用以驱动 LH 分泌过剩1。我们将评估沉默细胞系中的 GLUT1 后雄激素对葡萄糖摄取的影响并使用促性腺激素特异性 GLUT1 KO 小鼠以确定促性腺激素 GLUT1 在 PCOS 中的作用。在目标 2 中，我们将阐明 PCOS 诱导的炎症对促性腺激素代谢和功能的贡献。我们假设慢性炎症直接调节促性腺激素 LH 的分泌并有助于多囊卵巢综合症（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 特异性免疫表型，并使用以下方法评估免疫细胞对 PCOS 病因学的贡献免疫缺陷转基因小鼠模型。总之，这些目标将 1) 概述促性腺激素能量的作用生殖平衡和 PCOS，2) 解释雄激素如何增加 LH，以及 3) 识别特定的炎症途径作为 PCOS 的潜在治疗靶点。