Metabolic Events Controlling Ovarian Steroidogenesis

控制卵巢类固醇生成的代谢事件

• 批准号: 9240226
• 负责人: JOHN S DAVIS
• 金额: $ 14.99万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-11 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240226
• 关键词: Acute; Adenosine Monophosphate; Biological Models; Capsid Proteins; Cattle; Cell Differentiation process; Cells; Cholesterol; Contraceptive methods; Cyclic AMP-Dependent Protein Kinases; Development; Disease; Embryo; Endocrine; Energy-Generating Resources; Event; Fatty Acids; Fertility; Generations; Goals; Gonadotropins; Granulosa-Lutein Cells; Hormone Responsive; Hormones; Human; In Vitro; Knowledge; Length; Light; Lipids; Longevity; Luteal Cells; Luteal Phase; Luteinization; Luteinizing Hormone; Mammals; Metabolic; Modeling; Mono-S; Organelles; Ovarian; Ovarian Follicle; Ovary; Pituitary Gonadotropins; Population; Pregnancy; Pregnancy Maintenance; Pregnancy loss; Production; Progesterone; Protein Kinase; Proteins; Proteomics; Regulation; Research; Rodent; Role; Signal Transduction; Site; Somatic Cell; Source; Steroid biosynthesis; Steroids; Testing; Theca-Lutein Cells; Tissues; Up-Regulation; Woman; cell type; corpus luteum; design; experimental study; folliculogenesis; granulosa cell; hormone sensitivity; human tissue; in vitro Model; in vivo; innovation; insight; metabolomics; novel; novel strategies; novel therapeutic intervention; theca cell

The secretion of progesterone is a primary function of the corpus luteum (CL) and a prerequisite for normal maintenance of pregnancy in all mammals. The coordinated differentiation of granulosa cells (GC) and theca cells (TC) into a functional CL is required for fertility. The single most important factor involved in regulating the secretion of progesterone in the CL, irrespective of species, is luteinizing hormone (LH). This pituitary gonadotropin induces luteinization of GC and TC, formation of the CL, and is capable of extending the functional life span of the CL. Secretion of progesterone is absolutely required for establishment and maintenance of pregnancy and inadequate progesterone secretion contributes to early pregnancy loss in women and cattle, the two model systems employed in this project. Despite substantial scientific progress achieved in understanding the initial events leading to the differentiation of granulosa cells, little is known about the differentiation of theca cells into functional luteal cells. This incomplete knowledge interferes with the development of novel therapeutic interventions to enhance CL function (steroidogenesis), provide contraception, and ultimately to control fertility. Recent developments in other fields of research have shed light on the composition and role of intracellular lipid droplets as dynamic contributors to metabolic events and disease states. These understudied organelles are prominent components of steroidogenic cells but almost nothing is known about their role in the ovary. Despite their differences, both GC and TC accumulate lipid droplets (LD) during CL formation, presumptively for storage of the steroid precursor, cholesterol, and cellular energy in the form of fatty acids. The composition and precise function of LDs likely differs between these two cells because of their unique origins and functions. There is a gap in our knowledge of the formation, composition, and function of LDs in ovarian steroidogenic cells. This proposal will test the hypothesis that LDs provide a metabolic or hormone-sensitive organelle which can provide cellular energy and/or store and mobilize substrate for progesterone synthesis. We will employ state-of-the-art lipidomic, metabolomics and proteomic analysis to examine LDs and metabolic events driven by LH in differentiating bovine granulosa cells and theca cells and human granulosa-luteal cells. Experiments will determine the role of protein kinase A (PKA) and adenosine monophosphate activated protein kinase (AMPK) in controlling cellular metabolic activities that either enhance or inhibit progesterone synthesis. Our long-term objectives are to fully understand the cellular mechanisms of action of gonadotropins and the regulation of steroidogenesis. The short-term goals of this research are to discover new signaling events initiated by LH and to determine how these novel mechanisms contribute to innovative strategies for enhancing progesterone synthesis, fertility, and contraception.

黄体酮的分泌是黄体 (CL) 的主要功能，也是正常生长的先决条件。 所有哺乳动物的妊娠维持。颗粒细胞（GC）和卵泡膜的协调分化 细胞 (TC) 转化为功能性 CL 是生育能力所必需的。参与调节的最重要因素 无论物种如何，CL 中分泌的黄体酮都是黄体生成素 (LH)。这个垂体 促性腺激素诱导 GC 和 TC 黄体化，形成 CL，并且能够延长 CL 的功能寿命。黄体酮的分泌对于建立和发育是绝对必需的。 维持妊娠和黄体酮分泌不足会导致早期妊娠流产 妇女和牛是该项目中使用的两个模型系统。尽管科学取得了重大进展 在理解导致颗粒细胞分化的初始事件方面取得的进展，人们知之甚少 关于卵泡膜细胞分化为有功能的黄体细胞。这种不完整的知识会干扰 开发新的治疗干预措施以增强 CL 功能（类固醇生成），提供 避孕，最终达到控制生育的目的。其他研究领域的最新进展已经 阐明细胞内脂滴的组成和作用作为代谢事件的动态贡献者 和疾病状态。这些未被充分研究的细胞器是类固醇生成细胞的重要组成部分，但 关于它们在卵巢中的作用几乎一无所知。尽管存在差异，GC 和 TC 都会累积 CL 形成过程中的脂滴 (LD)，推测用于储存类固醇前体、胆固醇和 脂肪酸形式的细胞能量。 LD 的组成和精确功能可能有所不同 这两种细胞因其独特的起源和功能。我们对形成的认识存在差距， 卵巢类固醇生成细胞中LD的组成和功能。该提案将检验 LD 的假设 提供代谢或激素敏感的细胞器，其可以提供细胞能量和/或储存和 动员黄体酮合成的底物。我们将采用最先进的脂质组学、代谢组学和 蛋白质组学分析检查 LH 驱动的 LD 和代谢事件以区分牛颗粒 细胞和卵泡膜细胞以及人颗粒黄体细胞。实验将确定蛋白激酶的作用 A (PKA) 和单磷酸腺苷激活蛋白激酶 (AMPK) 控制细胞代谢 增强或抑制黄体酮合成的活性。我们的长期目标是充分 了解促性腺激素的细胞作用机制和类固醇生成的调节。这 这项研究的短期目标是发现 LH 发起的新信号事件并确定如何 这些新机制有助于增强黄体酮合成、生育能力的创新策略， 和避孕。