Signaling mechanisms that regulate meiosis in mammalian oocytes

调节哺乳动物卵母细胞减数分裂的信号机制

• 批准号: 7616729
• 负责人: LISA M MEHLMANN
• 金额: $ 25.9万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616729
• 关键词: AKT Signaling Pathway; Address; Adenylate Cyclase; Affect; Area; Arrestins; Basic Science; Cell membrane; Cells; Clinic; Clinical; Collaborations; Cyclic AMP; Development; Down-Regulation; Event; Fertility; Fertilization in Vitro; Figs - dietary; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gap Junctions; Goals; Human; Hydrolysis; In Vitro; Lead; Ligands; Luteinizing Hormone; Maintenance; Mammals; Mediating; Meiosis; Meiotic Prophase I; Methods; Microinjections; Mus; Oocytes; Ovary; Pathway interactions; Phosphotransferases; Physiological; Pituitary Gland; Process; Production; Proteins; Proto-Oncogene Proteins c-akt; RGS Proteins; RGS2 gene; Regulation; Reproductive Biology; Reproductive Physiology; Research; Research Personnel; Rodent; Rodent Model; Signal Pathway; Signal Transduction; Staging; Techniques; Woman; Women' s Health; Work; base; desensitization; egg; falls; improved; interest; oocyte maturation; phosphoric diester hydrolase; programs; response

DESCRIPTION (provided by applicant): The goal of this research is to examine the signaling events regulating meiotic progression in mammalian oocytes. Immature oocytes are arrested at prophase I, and in response to a surge of luteinizing hormone LH) that acts on the follicle cells, they re-enter meiosis and mature into eggs. The mechanism(s) by which LH transmits its signal from the follicle cells to the oocyte is not known. Aim 1 of this proposal will examine signaling mechanisms by which LH initiates meiotic resumption in mouse oocytes. Prior to the LH surge, meiotic arrest requires a high level of cAMP in the oocyte; this cAMP is produced by the G-protein coupled receptor GPRS, in the oocyte plasma membrane, that stimulates Gs to activate adenylate cyclase. In response to LH, cAMP levels in the oocyte fall, leading to meiotic resumption. Potential targets in the oocyte by which LH could act include the following: 1) GPR3, which could be turned off through the activation of G- protein receptor kinases (GRKs) and li-arrestins, a common mechanism for downregulating most GPCRs. 2) Gs, the activity of which could be inhibited by a regulator of G-protein signalling (RGS) protein. 3) The AKT/PKB signalling pathway, which has been shown to affect meiotic resumption in a variety of species. 4) Regulation at the level of gap junctions. These pathways will be investigated using recently developed methods for microinjecting follicle-enclosed oocytes. Aim 2 will examine if meiotic arrest and resumption in human oocytes depend on the same pathways as in rodent oocyte, by examining if human oocytes contain the same components of these signalling pathways. Aim 2 will also characterize cytoplasmic events that normally occur during human oocyte maturation. These studies will provide valuable information about which aspects of rodent models can be applied to human oocytes. The question of how meiosis is regulated is highly relevant to issues of women's health. In particular, it is of high interest clinically to develop methods for successfully maturing immature human oocytes in vitro, which could lead to improvements in in vitro fertilization treatments, as well as provide more options than are currently available for women to preserve their fertility. Improvements in in vitro maturation will require an understanding of all stages of meiotic arrest and the physiological mechanisms regulating the initiation of oocyte maturation. The proposed studies will contribute to the basic science background that underlies such clinical advances.

描述（由申请人提供）：本研究的目的是检查哺乳动物卵母细胞减数分裂进程的信号事件。未成熟的卵母细胞被阻滞在前期I，并响应于作用于卵泡细胞的促黄体激素LH的激增，它们重新进入减数分裂并成熟为卵子。LH将其信号从卵泡细胞传递到卵母细胞的机制尚不清楚。本提案的目标1将研究LH启动小鼠卵母细胞减数分裂恢复的信号机制。在LH峰之前，减数分裂停滞需要卵母细胞中高水平的cAMP;该cAMP由卵母细胞质膜中的G蛋白偶联受体GPRS产生，其刺激Gs以激活腺苷酸环化酶。作为对LH的反应，卵母细胞中的cAMP水平下降，导致减数分裂恢复。卵母细胞中LH可以起作用的潜在靶标包括以下：1）GPR 3，其可以通过G蛋白受体激酶（GRK）和I-抑制蛋白的激活而被关闭，这是下调大多数GPCR的常见机制。2)Gs，其活性可被G蛋白信号调节蛋白（RGS）抑制。3)AKT/PKB信号通路已被证明影响多种物种的减数分裂恢复。4)间隙连接水平的调节。这些途径将使用最近开发的显微注射卵泡封闭的卵母细胞的方法进行研究。目的2将通过检查人类卵母细胞是否含有这些信号通路的相同组分来检查人类卵母细胞中减数分裂停滞和恢复是否依赖于与啮齿动物卵母细胞相同的通路。目标2也将描述在人卵母细胞成熟过程中通常发生的细胞质事件。这些研究将提供有关啮齿动物模型的哪些方面可以应用于人类卵母细胞的有价值的信息。减数分裂是如何调节的问题与妇女的健康问题密切相关。特别是，临床上高度关注的是开发用于在体外成功地使未成熟的人类卵母细胞成熟的方法，这可能导致体外受精治疗的改进，以及为女性提供比目前可用的更多的选择以保持其生育能力。体外成熟的改进需要了解减数分裂停滞的所有阶段和调节卵母细胞成熟起始的生理机制。拟议的研究将有助于这些临床进展的基础科学背景。