Signaling Pathways Regulating Ovarian Follicle Formation

调节卵巢卵泡形成的信号通路

• 批准号: 7763055
• 负责人: KELLY E MAYO
• 金额: $ 36.34万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7763055
• 关键词: Activins; Adult; Affect; Agonist; Apoptosis; Basic Science; Cell Communication; Cell Death; Cell Proliferation; Cell physiology; Development; Disease; Environment; Estrogens; Follistatin; Gene Expression Profiling; Gene Targeting; Germ Cells; Giant Cells; Health; Hormonal; Human; Infertility; Knock-out; Knockout Mice; Ligands; Mediating; Mus; Neonatal; Notch Signaling Pathway; Oocytes; Organogenesis; Ovarian; Ovarian Follicle; Ovary; Ovulation; Pathway interactions; Play; Pregnancy Outcome; Primordial Follicle; Process; Regulation; Reporter; Reproductive Health; Research; Role; Signal Pathway; Signal Transduction; Somatic Cell; Supporting Cell; System; Testing; granulosa cell; notch protein; novel; receptor; research study; zygote

A fundamental determinant of a successful pregnancy outcome is the quality of the oocyte that will be fertilized to form the zygote. The health of the oocyte is, in turn, a direct reflection of the follicle environment and the interactions between germ cells and somatic support cells that nurture the oocyte to ovulation. The studies proposed invesfigate the formation of the ovarian follicle, and are applicable to understanding how the health of the oocyte is maintained and how aberrations in follicle assembly might contribute to infertility. This research investigates roles for key developmental signaling pathways in the establishment of the inifial follicle pool. During ovarian organogenesis, germ cell syncytia, or 'nests' undergo breakdown to form the primordial follicles that will support reproducfion in the adult. Agents that disrupt breakdown of germ cell nests and follicle formation have adverse impacts on reproductive health. Our studies and those of others idenfify Notch, activin and estrogen signaling as being important for germ cell nest breakdown and normal follicle formation in the ovary, and furthermore reveal that mis-regulation of these pathways results in the formation of aberrant follicles. We hypothesize that each of these signals play important but distinct roles in follicle formation, with 1) Notch regulafing granulosa-germ cell interactions and promoting granulosa cell identity, 2) acfivin sfimulafing granulosa cell proliferafion, and 3) estrogen inhibifing nest breakdown in part through its cross-regulation of Notch and activin signaling. We propose to investigate these novel roles, as well as to examine the integrafion of these signaling pathways in the neonatal mouse ovary. Aim 1 will ufilize a novel ex vivo ovary culture system as well as conditional knockout mice to investigate mechanisms by which Notch signaling regulates somatic pre-granulosa cell function and facilitates germ cell nest breakdown and follicle formafion. Aim 2 will utilize the ovarian culture system, as well as gene expression profiling approaches, to establish mechanisms and target genes by which activin signaling regulates ovarian cell death or proliferation and enhances follicle formation. Aim 3 will examine cross-regulation between these signaling pathways to determine if the repressive effects of estrogen on germ cell nest breakdown are mediated by interacfions with the Notch and activin signaling pathways. Studies invesfigafing the signaling pathways that regulate germ cell and somatic cell functions and interactions in the developing ovary, processes which impact the formation of follicles capable of maturing and ovulafing a healthy oocyte, will certainly enhance our ability to identify, understand and eventually treat diseases or disorders that adversely affect follicle health and pregnancy outcome. We anticipate that the basic research studies described in this proposal will contribute to that important effort and will eventually advance human reproductive health.

成功妊娠的一个基本决定因素是将被受精的卵母细胞的质量。 受精形成合子。卵母细胞的健康反过来又直接反映了卵泡环境 以及生殖细胞和体细胞支持细胞之间的相互作用，体细胞支持细胞培养卵母细胞排卵。的 研究提出调查卵泡的形成，并适用于了解如何 卵母细胞的健康得以维持，以及卵泡组装中的异常如何导致不育。 本研究探讨了关键的发育信号通路在建立初始发育阶段中的作用。 卵泡池在卵巢器官发生过程中，生殖细胞合胞体或“巢”经历分解， 支持成年人生殖的原始卵泡。破坏生殖细胞分解的药物 巢和卵泡的形成对生殖健康有不利影响。我们和其他人的研究 证实Notch、激活素和雌激素信号对生殖细胞巢破裂和正常发育至关重要 卵泡形成的卵巢，并进一步揭示，这些途径的错误调节，结果在 形成异常卵泡。我们假设，这些信号中的每一个都发挥着重要但不同的作用， 卵泡形成，1）Notch调节颗粒细胞-生殖细胞相互作用，促进颗粒细胞 同一性，2）acfivin sfimulafing颗粒细胞增殖，3）雌激素抑制巢破坏部分 通过其对Notch和激活素信号的交叉调节。我们建议调查这些新的角色，因为 并检测这些信号通路在新生小鼠卵巢中的整合。目标1将使用 一种新的离体卵巢培养系统以及条件性敲除小鼠， 其中Notch信号调节体细胞前颗粒细胞功能并促进生殖细胞巢破裂 和卵泡形成。目的2将利用卵巢培养系统，以及基因表达谱 方法，建立激活素信号调节卵巢细胞的机制和靶基因， 死亡或增殖并促进卵泡形成。目标3将研究这些之间的交叉监管 信号通路，以确定是否抑制作用的雌激素对生殖细胞巢崩溃， 通过与Notch和激活素信号通路的相互作用介导。信号转导研究 调节生殖细胞和体细胞功能以及发育中卵巢相互作用的途径， 影响能够使健康卵母细胞成熟和排卵的卵泡形成的过程将 这无疑会增强我们识别、理解并最终治疗那些对我们的健康不利的疾病或病症的能力。 影响卵泡健康和妊娠结局。我们预计，本报告所述的基础研究 这些建议将有助于这一重要努力，并最终促进人类生殖健康。