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; 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.

孕激素的分泌是叶酸肠胃（CL）的主要功能，也是正常的先决条件 在所有哺乳动物中维持怀孕。颗粒细胞（GC）和THECA的协调分化 生育能力需要细胞（TC）进入功能性CL。调节涉及的最重要的因素 CL中孕酮的分泌，无论物种如何，是黄体生成激素（LH）。这个垂体 促性腺激素诱导GC和TC的黄体化，CL的形成，并能够延伸 CL的功能寿命。孕酮的分泌是绝对需要的 维持怀孕和孕激素分泌不足会导致早期妊娠丧失 妇女和牛，该项目中采用的两个模型系统。尽管有很大的科学进步 在理解导致颗粒细胞分化的最初事件时，几乎没有知道 关于将蛋白蛋白细胞分化为功能性黄很好细胞。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），提供 避孕，最终控制生育能力。其他研究领域的最新发展已经消失 对细胞内脂质液滴的组成和作用作为代谢事件的动态贡献者 和疾病状态。这些研究的细胞器是类固醇生成细胞的突出组成部分，但 他们在卵巢中的作用几乎一无所知。尽管差异有所不同，但GC和TC都积累 CL形成过程中脂质液滴（LD），假定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不同 这两个细胞由于其独特的起源和功能。我们对形成的知识存在差距， LDS在卵巢类固醇生成细胞中的组成和功能。该提案将检验以下假设 提供代谢或激素敏感的细胞器，该细胞器可以提供细胞能量和/或存储，并且 动员底物进行孕激素合成。我们将采用最先进的脂肪组，代谢组学和 蛋白质组学分析检查LH在区分牛颗粒中驱动的LD和代谢事件 细胞和theca细胞以及人颗粒 - 乳腺细胞。实验将确定蛋白激酶的作用 A（PKA）和腺苷单磷酸激活的蛋白激酶（AMPK）在控制细胞代谢中 增强或抑制孕酮合成的活性。我们的长期目标是完全 了解促性腺激素作用的细胞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 这些新型机制有助于增强孕激素合成，生育能力的创新策略 和避孕。