Metabolic Regulators of Corpus Luteum Function

摘要 黄体是一种短暂的内分泌腺，其结构和功能受两者的调节 刺激黄体功能的黄体营养因子和抑制黄体功能的黄体溶解因子。CL是最重要的 发情或月经周期和怀孕早期孕酮的主要来源。如果怀孕有影响 不发生时，CL需要及时消退才能恢复正常发情或月经周期。单曲 最重要的因素涉及调节黄体中孕酮的分泌，不分物种， 是黄体生成素(LH)。这种垂体促性腺激素诱导CL的形成，并能够 延长CL的使用寿命。孕酮的分泌绝对是建立所必需的 维持妊娠和孕酮分泌不足会导致早孕丢失 在妇女和牛中，这两个模式系统在本项目中使用。女性生殖受以下因素影响 据估计，超过一半的育龄妇女超重或肥胖。最新研究 提示体重增加可能导致灵长类CL功能受损。其他方面的最新发展 研究领域揭示了细胞内脂滴(LD)的组成和作用 代谢事件和疾病状态的贡献者。这些未被研究的细胞器是突出的。 类固醇生成细胞的成分，但几乎不知道它们在卵巢中的作用，特别是 它们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形成过程中积累，可能是为了储存 类固醇前体、胆固醇和以脂肪酸形式存在的细胞能量。我们的初步数据显示 脂滴可能是黄体细胞类固醇合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。 我们对低密度脂蛋白在卵巢类固醇激素生成中的形成、组成和功能的认识还存在空白。 细胞。这项提议将检验LDS提供代谢或激素敏感细胞器的假设 可以提供细胞能量和/或储存和动员孕酮合成的底物。此外，我们 假设天然黄体生成素PGF2α在体内迅速干扰LD动力学，导致急性 抑制类固醇合成。该项目将使用最先进的脂质组学和蛋白质组学分析来 牛黄体细胞和人黄体颗粒细胞中促黄体生成素或前列腺素F_2α驱动的低密度脂蛋白及其代谢事件 细胞。我们的长期目标是全面了解促性腺激素和 对生育的调节。这项研究的短期目标是发现新发起的信令事件 并确定这些新的机制如何有助于创新的战略 促进孕酮合成。该项目将提供新的基础知识(源自脂质组学 和蛋白质组学方法)有关卵巢脂滴和细胞代谢事件，预计 提出黄体功能调控机制的重大概念性突破。

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.