Metabolic Regulators of Corpus Luteum Function

总结 黄体是一个短暂的内分泌腺体，其结构和功能受两者的调节 刺激黄体功能的促黄体因子和抑制黄体功能的溶黄体因子。CL是 在动情期或月经周期和怀孕早期孕酮的主要来源。如果怀孕 如果没有发生，则需要CL及时消退以恢复正常的发情或月经周期。单 参与调节CL中孕酮分泌的最重要因素，与物种无关， 是促黄体生成激素（LH）。这种垂体促性腺激素诱导CL的形成，并且能够 延长CL的功能寿命。孕激素的分泌是绝对必要的建立 维持妊娠和孕酮分泌不足导致早期妊娠丢失 在妇女和牛方面，本项目采用了两种示范系统。女性生殖受到 据估计，超过一半的育龄妇女超重或肥胖。最近的研究 表明体重增加可能导致灵长类动物CL功能受损。其他领域的最新发展 研究领域已经阐明了细胞内脂滴（LD）的组成和作用， 代谢事件和疾病状态的贡献者。这些未被充分研究的细胞器 类固醇生成细胞的组成部分，但几乎没有什么是知道他们在卵巢中的作用，特别是 在黄体功能中的作用。更深入地了解CL的代谢调节具有重要意义。 对提高生育率的影响。脂滴在CL形成期间积聚，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。我们的初步数据显示 脂滴可能作为黄体细胞类固醇生成和代谢的信号平台。 此外，脂滴似乎受到促黄体激素和促黄体激素的不同调节。 我们对卵巢类固醇激素合成中LDs的形成、组成和功能的认识还存在空白。 细胞这一提议将检验LD提供代谢或代谢敏感性细胞器的假设， 可提供细胞能量和/或储存和动员孕酮合成的底物。而且我们 假设天然溶血素PGF 2 α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， 检查牛黄体细胞和人颗粒黄体细胞中LH或PGF 2 α驱动的LD和代谢事件 细胞我们的长期目标是充分了解促性腺激素的细胞作用机制， 生育率的调节这项研究的短期目标是发现新的信号事件启动 通过LH和PGF 2 α，并确定这些新的机制如何有助于创新策略， 促进孕酮合成。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）关于卵巢脂滴和细胞代谢事件，预计 在控制黄体功能的机制方面取得重大的概念突破。

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.