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.

孕酮的分泌是黄体（CL）的主要功能，也是正常妊娠的先决条件。 在所有哺乳动物中维持妊娠。颗粒细胞和卵泡膜的协调分化 细胞（TC）转化为功能性CL是生育所必需的。参与调节的最重要的因素 CL中分泌的孕酮，与物种无关，是促黄体生成激素（LH）。这个脑垂体 促性腺激素诱导GC和TC的黄素化，CL的形成，并能够延长 CL的功能寿命。孕激素的分泌是建立和 维持妊娠和孕酮分泌不足导致早期妊娠丢失， 妇女和牛，这两个模型系统在这个项目中使用。尽管科学取得了巨大的进步 尽管在理解导致颗粒细胞分化的初始事件方面取得了很大进展， 关于卵泡膜细胞分化成功能性黄体细胞。这种不完整的知识干扰了 开发新的治疗干预措施以增强CL功能（类固醇生成）， 避孕，最终控制生育。其他研究领域的最新发展使 细胞内脂滴作为代谢事件的动态贡献者的组成和作用的光 和疾病状态。这些未充分研究的细胞器是类固醇生成细胞的重要组成部分， 关于它们在卵巢中的作用几乎一无所知。尽管GC和TC存在差异， CL形成期间的脂滴（LD），推测用于储存类固醇前体、胆固醇， 以脂肪酸的形式提供细胞能量。LD的组成和精确功能可能在以下方面不同： 这两种细胞因其独特的起源和功能而异。我们对这个构造的了解还存在空白， 组成和功能的LD在卵巢类固醇生成细胞。这一提议将检验LD 提供代谢或代谢敏感性细胞器，其可以提供细胞能量和/或储存， 动员孕酮合成的底物。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，以检查区分牛颗粒层中LH驱动的LD和代谢事件 细胞和卵泡膜细胞和人颗粒黄体细胞。实验将确定蛋白激酶的作用 蛋白激酶A（PKA）和腺苷酸活化蛋白激酶（AMPK）在细胞代谢调控中的作用 增强或抑制孕酮合成的活性。我们的长期目标是全面 了解促性腺激素作用的细胞机制和类固醇生成的调节。的 本研究的短期目标是发现LH启动的新信号事件，并确定如何 这些新的机制有助于提高孕酮合成，生育力， 和避孕。