Metabolic Regulators of Corpus Luteum Function

黄体功能的代谢调节剂

• 批准号: 9358300
• 负责人: JOHN S DAVIS
• 金额: $ 32.08万
• 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: 2017-08-03 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9358300
• 关键词: Acute; Affect; Age; Assisted Reproductive Technology; Biological Models; Cattle; Cell Differentiation process; Cells; Cholesterol; Contraceptive methods; Data; Development; Disease; Embryo; Endocrine; Endocrine Glands; Estrous Cycle; Event; Fatty Acids; Female; Fertility; Funding Opportunities; Goals; Gonadotropins; Granulosa-Lutein Cells; Hormone Responsive; Hormones; Human; Impairment; In Vitro; Knowledge; Length; Light; Lipids; Longevity; Luteal Cells; Luteal Phase; Luteinization; Luteinizing Hormone; Luteolysis; Menstrual cycle; Metabolic; Metabolism; Modeling; Mono-S; Obesity; Organelles; Ovarian; Ovarian Cycles; Ovary; Overweight; Ovulation; Periodicity; Pituitary Gonadotropins; Population; Pregnancy; Pregnancy Maintenance; Pregnancy loss; Primates; Process; Production; Progesterone; Prostaglandins; Proteomics; Regulation; Reproduction; Research; Role; Signal Transduction; Source; Steroid biosynthesis; Steroids; Structure; Testing; Theca-Lutein Cells; Time; Tissues; Triglycerides; Weight Gain; Woman; cell type; corpus luteum; design; fertility improvement; folliculogenesis; granulosa cell; hormone sensitivity; human tissue; improved; in vitro Model; in vivo; innovation; insight; novel; reproductive; theca cell

SUMMARY The corpus luteum (CL) is a transient endocrine gland whose structure and function are regulated by both luteotrophic factors that stimulate luteal function and luteolytic factors that inhibit luteal function. The CL is the primary source of progesterone during estrous or menstrual cycles and early pregnancy. If pregnancy does not occur, timely regression of the CL is required to resume normal estrous or menstrual cycles. 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 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. Female reproduction is affected by obesity and it is estimated that over half of reproductive age women are overweight or obese. Recent research suggests that weight gain can contribute to impaired function of the primate CL. Recent developments in other fields of research have shed light on the composition and role of intracellular lipid droplets (LD) as significant 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 and specifically their role in luteal function. A deeper understanding of the metabolic regulation of the CL has important implications for improving fertility. Lipid droplets accumulate during CL formation, presumptively for storage of the steroid precursor, cholesterol, and cellular energy in the form of fatty acids. Our preliminary data indicate that the lipid droplet may serve as a signaling platform for steroidogenesis and metabolism in the luteal cell. Furthermore the lipid droplet appears to be differentially regulated by luteotrophic and luteolytic hormones. 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. Furthermore, we hypothesize that the natural luteolysin PGF2α rapidly disrupts LD dynamics in vivo resulting in an acute inhibition of steroidogenesis. The project will employ state-of-the-art lipidomics and proteomics analysis to examine LDs and metabolic events driven by LH or PGF2α in bovine luteal cells and human granulosa-luteal cells. Our long-term objectives are to fully understand the cellular mechanisms of action of gonadotropins and the regulation of fertility. The short-term goals of this research are to discover new signaling events initiated by LH and PGF2α and to determine how these novel mechanisms contribute to innovative strategies for enhancing progesterone synthesis. The project will provide novel basic knowledge (derived from lipidomics and proteomic approaches) about ovarian lipid droplets and cellular metabolic events that are expected to advance a major conceptual breakthrough about the mechanisms controlling luteal function.

概括 黄体（CL）是一种短暂的内分泌腺，其结构和功能受两者调节 刺激黄体功能的黄体营养因子和抑制黄体功能的黄体分解因子。 发情或月经周期以及怀孕早期（如果怀孕）的黄体酮的主要来源。 如果没有发生，则需要及时使 CL 消退以恢复正常的动情或月经周期。 调节 CL 中黄体酮分泌的最重要因素，无论物种如何， 是黄体生成素 (LH)，这种垂体促性腺激素可诱导 CL 的形成，并且能够 延长 CL 的功能寿命 黄体酮的分泌对于建立是绝对必要的。 维持妊娠和黄体酮分泌不足会导致早期流产 在妇女和牛中，该项目采用的两个模型系统受到女性生殖的影响。 肥胖，据估计超过一半的育龄妇女超重或肥胖。 表明体重增加可能导致灵长类动物 CL 功能受损。 研究领域揭示了细胞内脂滴（LD）的组成和作用，具有重要意义 这些未被充分研究的细胞器是代谢事件和疾病状态的重要贡献者。 类固醇生成细胞的成分，但对其在卵巢中的作用几乎一无所知，特别是 深入了解 CL 的代谢调节具有重要意义。 脂质滴在 CL 形成过程中积累，推测是为了储存。 我们的初步数据表明，类固醇前体、胆固醇和脂肪酸形式的细胞能量。 脂滴可能作为黄体细胞中类固醇生成和代谢的信号平台。 此外，脂滴似乎受到黄体营养激素和黄体分解激素的不同调节。 我们对 LDs 在卵巢类固醇生成中的形成、组成和功能的了解存在差距 该提案将检验 LD 提供代谢或激素敏感细胞器的假设。 可以提供细胞能量和/或储存和动员黄体酮合成的底物。 随后，天然木黄素溶血素 PGF2α 迅速破坏体内 LD 动力学，导致急性 该项目将采用最先进的脂质组学和蛋白质组学分析来抑制类固醇生成。 检查牛黄体细胞和人颗粒黄体中 LH 或 PGF2α 驱动的 LD 和代谢事件 我们的长期目标是充分了解促性腺激素和细胞的作用机制。 这项研究的短期目标是发现引发的新信号事件。 LH 和 PGF2α 并确定这些新机制如何有助于创新策略 该项目将提供新的基础知识（来自脂质组学）。 和蛋白质组学方法）有关卵巢脂滴和细胞代谢事件，预计 关于黄体功能控制机制的重大概念突破。