Metabolic Regulators of Corpus Luteum Function

黄体功能的代谢调节剂

• 批准号: 10155086
• 负责人: JOHN S DAVIS
• 金额: $ 30.41万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155086
• 关键词: Acute; Affect; Age; Assisted Reproductive Technology; Biological Models; Cattle; Cell Differentiation process; Cells; Cholesterol; Contraceptive methods; Data; Development; Disease; Embryo; Embryo Loss; 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; Obesity; Organelles; Ovarian; Ovarian Cycles; Ovary; Overweight; Ovulation; Periodicity; Pituitary Gonadotropins; Population; Pregnancy; Pregnancy Maintenance; 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; early pregnancy; early pregnancy loss; fertility improvement; folliculogenesis; granulosa cell; hormone sensitivity; human tissue; improved; in vitro Model; in vivo; innovation; insight; lipidomics; 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 Luteum（Cl）是一种瞬态内分泌腺，其结构和功能都由两者调节 刺激黄素功能和抑制黄体功能的黄褐色功能的葡萄糖营养因子。 CL是 孕酮的主要来源或月经周期和早期怀孕。如果怀孕 没有发生，需要及时的CL回归才能恢复正常的发情或月经周期。单人 在CL中调节孕酮分泌的最重要因素，无论物种如何， 是亮叶骑马（LH）。这种狂热的促性腺激素可诱导CL的形成，并且能够 扩展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 在妇女和牛中，该项目采用的两个模型系统。女性繁殖受到 肥胖症，据估计，超过一半的生殖年龄妇女超重或肥胖。最近的研究 表明体重增加会导致灵长类动物CL的功能受损。其他方面的最新发展 研究领域已经阐明了细胞内脂质液滴（LD）的组成和作用 代谢事件和疾病状态的贡献者。这些理解的细胞器是突出的 类固醇生成细胞的成分，但几乎什么都不了解它们在卵巢中的作用，特别是 它们在黄体功能中的作用。对CL的代谢调节的更深入了解具有重要的 改善生育能力的影响。脂质液滴在CL形成过程中积聚，大概是用于存储 类固醇前体，胆固醇和细胞能的形式。我们指示的初步数据 脂质液滴可以用作黄体细胞中类固醇生成和代谢的信号平台。 此外，脂质液滴似乎受到葡萄糖和黄褐色溶解激素的差异调节。 我们对卵巢类固醇生成中LD的形成，组成和功能的了解存在差距 细胞。该建议将检验以下假设：LD提供代谢或对马敏感的细胞器 可以提供细胞能量和/或储存并动员底物以进行孕激素合成。此外，我们 假设天然叶黄素PGF2α迅速破坏体内LD动力学，导致急性 抑制类固醇生成。该项目将采用最先进的脂质组学和蛋白质组学分析来 检查LH或PGF2α在牛黄叶细胞和人颗粒状葡萄糖中驱动的LDS和代谢事件 细胞。我们的长期目标是充分了解促性腺激素和 生育能力的调节。这项研究的短期目标是发现发起的新信号事件 通过LH和PGF2α，并确定这些新型机制如何促进创新策略 增强孕酮合成。该项目将提供新颖的基本知识（源自脂质瘤 和蛋白质组学方法）关于卵巢脂质液滴和细胞代谢事件的预期 提出有关控制黄体功能的机制的重大概念突破。

项目成果

Attainment and maintenance of pubertal cyclicity may predict reproductive longevity in beef heifers†.

青春期周期的实现和维持可以预测肉牛的繁殖寿命。

• DOI: 10.1093/biolre/ioab044
• 发表时间: 2021
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: Nafziger,SarahR;Tenley,SarahC;Summers,AdamF;Abedal-Majed,MohamedA;Hart,Mariah;Bergman,JeffreyW;Kurz,ScottG;Davis,JohnS;Wood,JenniferR;Cupp,AndreaS
• 通讯作者: Cupp,AndreaS

Mechanisms of angioregression of the corpus luteum.

• DOI: 10.3389/fphys.2023.1254943
• 发表时间: 2023
• 期刊: Frontiers in physiology
• 影响因子: 4

Luteal Lipid Droplets: A Novel Platform for Steroid Synthesis.

黄体脂滴：类固醇合成的新平台。

• DOI: 10.1210/endocr/bqad124
• 发表时间: 2023
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Plewes,MicheleR;Talbott,HeatherA;Saviola,AnthonyJ;Woods,NicholasT;Schott,MicahB;Davis,JohnS
• 通讯作者: Davis,JohnS

Triennial Reproduction Symposium: Looking back and moving forward-how reproductive physiology has evolved.

三年一度的生殖研讨会：回顾与展望——生殖生理学的演变。

• DOI: 10.1093/jas/sky148
• 发表时间: 2018
• 期刊: Journal of animal science
• 影响因子: 3.3
• 作者: Hamernik,DebL;Cupp,AndreaS;Davis,JohnS
• 通讯作者: Davis,JohnS