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 了解排卵和随后的叶黄素（CL）形成的细胞事件是 至关重要，因为这些生物学过程为我们调节女性的能力提供了基础 生育能力。卵巢前促性蛋白激增引起的细胞事件的基本基石至关重要 对于排卵和CL的形成是特定转录因子的表达。但是，我们对 促性腺激素引起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剂蛋白-1（AP-1）转录因子家族的成员FOS （又称C-Fos），是涉及卵泡发育，排卵和黄体形成的关键转录因子。 即使施用外源性促性腺激素，FOS缺乏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。但是，很少 毫无疑问，FOS/AP-1转录因子如何影响卵巢中的这些过程。我们的 初步研究首次揭示了FOS的表达高度上调 HCG在正常骑自行车妇女和在HCG后的卵泡中收集的卵泡 在小鼠中给药。此外，我们证明了FOS调节了HCG诱导的增加 通过直接与这些启动子结合的人颗粒细胞中关键排卵基因的表达 基因。根据这些新发现的结果，我们假设FOS/AP-1在排卵和 人类和小鼠的黄体形成/功能。 FOS NULL小鼠表现出一种多效性表型，出生时生存力显着丧失。确定 FOS/AP-1的卵巢特异性功能/作用，我们建议建立新型的转基因小鼠模型，其中 FOS表达以卵巢细胞特异性方式消融。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（特定目标＃1）。相互关联和比较 从小鼠到人类的发现，我们将首先表征所有FOS的时空调节表达 和在整个卵泡之前获得的排卵卵泡中的Jun家族成员。 通常是骑自行车的女人。 FOS/AP-1在人卵巢中的具体作用也将通过识别 FOS/AP-1的下游靶基因并评估FOS作用的细胞影响（特定目标＃2）。 从拟议的研究中获得的信息不仅会促进我们对 成功排卵和黄体的必要机制，但也有助于未来 翻译/临床应用，从而改善了体内和体外生育能力的治疗。