The Role of FOS in the Ovary

低聚果糖 (FOS) 在卵巢中的作用

• 批准号: 9925796
• 负责人: MISUNG JO
• 金额: $ 41.32万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-06 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925796
• 关键词: Address; Affect; Albers-Schonberg disease; Binding; Binding Sites; Biological Process; Birth; Cell Culture Techniques; Cells; DNA Binding; Data; Development; Event; Exhibits; FOS gene; Family; Family member; Fertility; Foundations; Future; Gene Expression; Genes; Gonadotropins; Hour; Human; Human Chorionic Gonadotropin; In Vitro; JUNB gene; Knockout Mice; Knowledge; Light; Luteinization; Mediating; Mus; Mutant Strains Mice; Ovarian; Ovarian Tissue; Ovary; Ovulation; PMSG (Gonadotropins); Pathway interactions; Phenotype; Physiological; Physiology; Pilot Projects; Play; Process; Progesterone Receptors; Prostaglandins; Reporting; Reproductive Health; Role; Time; Transcription Factor AP-1; Transgenic Mice; Woman; base; clinical application; corpus luteum; design; female fertility; granulosa cell; human tissue; improved; in vivo; insight; jun Oncogene; member; mouse model; novel; prevent; promoter; recombinase-mediated cassette exchange; spatiotemporal; transcription factor

Abstract Understanding the cellular events underlying ovulation and subsequent corpus luteum (CL) formation is critically important because these biological processes provide the foundation of our ability to regulate female fertility. A fundamental cornerstone of the cellular events induced by the preovulatory gonadotropin surge vital for ovulation and CL formation is the expression of specific transcription factors. However, our knowledge of the identity and regulatory actions of gonadotropin-induced key transcription factors remains limited. A recent study has shed light on a member of the activator protein-1 (AP-1) transcription factor family, FOS (a.k.a. c-fos), as a key transcription factor involved in follicular development, ovulation, and luteal formation. Fos-deficient mice failed to ovulate and form CL even when exogenous gonadotropins were administered (1), indicating that the ovarian expression of Fos is necessary for normal ovulation and luteinization. However, little to nothing is known exactly how the FOS/AP-1 transcription factor affects these processes in the ovary. Our preliminary study revealed for the first time that the expression of FOS is highly up-regulated in dominant follicles collected after hCG administration from normally cycling women and in preovulatory follicles after hCG administration in mice. Moreover, we demonstrated that FOS regulated the hCG-induced increase in the expression of key ovulatory genes in human granulosa cells by directly binding to the promoters of these genes. Based on these novel findings, we hypothesized that FOS/AP-1 plays essential roles in ovulation and luteal formation/function both in humans and mice. Fos null mice displayed a pleiotropic phenotype with significant loss of viability at birth. To determine the ovary-specific function/action of FOS/AP-1, we propose to establish novel transgenic mouse models in which Fos expression is ablated in an ovarian cell-specific manner. These mutant mice will be used to assess the ovarian phenotype including follicular development, ovulation, luteal development, and fertility as well as to identify downstream target genes of FOS/AP-1 in ovarian cells (Specific Aim #1). To relate and compare the findings from mice to humans, we will first characterize the spatiotemporally regulated expression of all FOS and JUN family members in ovulatory follicles obtained before and throughout the periovulatory period from normally cycling women. The specific role of FOS/AP-1 in human ovaries will also be determined by identifying downstream target genes of FOS/AP-1 and assessing the cellular impact(s) of FOS' action (Specific Aim #2). The information obtained from the proposed studies will not only advance our understanding of the mechanism necessary for successful ovulation and luteinization but also be instrumental for future translational/clinical application, thus leading to improved management of fertility in vivo and in vitro.

抽象的 了解排卵和随后黄体 (CL) 形成的细胞事件是 至关重要，因为这些生物过程为我们调节女性的能力奠定了基础 生育能力。排卵前促性腺激素激增诱导的细胞事件的基本基石至关重要 排卵和 CL 形成的关键是特定转录因子的表达。然而，我们的知识 促性腺激素诱导的关键转录因子的身份和调节作用仍然有限。 最近的一项研究揭示了激活蛋白 1 (AP-1) 转录因子家族的成员 FOS （又名 c-fos），作为参与卵泡发育、排卵和黄体形成的关键转录因子。 即使给予外源性促性腺激素，Fos 缺陷小鼠也无法排卵并形成 CL (1)， 表明Fos的卵巢表达对于正常排卵和黄体化是必需的。然而，很少 目前尚不清楚 FOS/AP-1 转录因子如何影响卵巢中的这些过程。我们的 初步研究首次揭示FOS在显性细胞中的表达高度上调 正常周期女性施用 hCG 后收集的卵泡以及 hCG 后在排卵前卵泡中收集的卵泡 在小鼠中给药。此外，我们证明 FOS 调节 hCG 诱导的 通过直接结合人颗粒细胞的启动子来表达关键排卵基因 基因。基于这些新发现，我们假设 FOS/AP-1 在排卵和 人类和小鼠的黄体形成/功能。 Fos缺失小鼠表现出多效性表型，出生时活力显着丧失。确定 FOS/AP-1 的卵巢特异性功能/作用，我们建议建立新型转基因小鼠模型，其中 Fos 表达以卵巢细胞特异性方式消除。这些突变小鼠将用于评估 卵巢表型，包括卵泡发育、排卵、黄体发育和生育能力以及 鉴定卵巢细胞中 FOS/AP-1 的下游靶基因（具体目标#1）。关联和比较 从小鼠到人类的研究结果，我们将首先描述所有 FOS 的时空调节表达 和 JUN 家族成员在排卵期之前和整个排卵期期间获得的排卵卵泡中 通常骑自行车的女性。 FOS/AP-1 在人类卵巢中的具体作用也将通过确定 FOS/AP-1 的下游靶基因并评估 FOS 作用的细胞影响（具体目标 #2）。 从拟议研究中获得的信息不仅将增进我们对 成功排卵和黄体化所必需的机制，而且对未来也有帮助 转化/临床应用，从而改善体内和体外生育力的管理。