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: 10462861
• 负责人: Dequina Angelina Nicholas
• 金额: $ 24.9万
• 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/10462861
• 关键词: Address; 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; 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; comorbidity; conditional knockout; 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; 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.

项目总结 多囊卵巢综合征(PCOS)是育龄妇女最常见的生育障碍。女人 患有多囊卵巢综合征的患者促性腺激素黄体生成素(LH)、雄激素、葡萄糖、游离脂肪酸(FFA)、 和炎性细胞因子。多囊卵巢综合征和多囊卵巢综合征患者的促黄体生成素和睾酮水平均随之升高 多囊卵巢综合征的小鼠模型与睾酮抑制神经内分泌的成熟范式相反 轴心。这一悖论背后的机制在很大程度上还没有被探索。黄体生成素的翻译和分泌是天生的能量- 从属进程。因此，促性腺激素细胞代谢可以解释这种反直觉的关系。 多囊卵巢综合征中雄激素(合成类固醇)和黄体生成素之间的关系。这项提案的总体目标是调查 促性腺激素葡萄糖代谢对黄体生成素分泌和生育力的影响，在正常和类似多囊卵巢综合征的条件下。 这一建议的首要假设是促性腺激素中的细胞代谢调节黄体生成素的合成； 与PCOS相关的因素，包括葡萄糖、雄激素和炎性细胞因子，扰乱促性腺激素 能量平衡，从而分泌黄体生成素。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黄体生成素的产生和分泌。 我们将在体外和体内测试缺糖对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 可利用性和黄体生成素分泌。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)击倒女性生育能力。在目标2中，我们将破译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促进促黄体生成素的分泌。 通过GLUT1的翻译调控。我们将评估雄激素对沉默后葡萄糖摄取的影响 用促性腺激素特异性GLUT1或雄激素受体KO小鼠确定Glut1在细胞系中的作用 促性腺激素GLUT1在多囊卵巢综合征中的表达。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 促性腺激素黄体生成素的分泌并导致多囊卵巢综合征患者的生殖功能障碍。使用复杂的生物信息学 方法，我们将鉴定PCOS的免疫表型，并评估免疫细胞的贡献 利用免疫缺陷转基因小鼠模型研究多囊卵巢综合征的病因学。总而言之，这些目标将勾勒出一个角色 对于多囊卵巢综合征的促性腺激素能量平衡，2)解释雄激素如何促进促黄体生成素，以及3)确定特定的 炎症通路是多囊卵巢综合征潜在的治疗靶点。在K99指导阶段，尼古拉斯博士将 接受生殖生理学和导师建立的多囊卵巢综合征小鼠模型的培训。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，以启动成功的职业解剖 炎症在生殖和代谢疾病中的作用。