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: 7478706
• 负责人: LISA M MEHLMANN
• 金额: $ 25.68万
• 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/7478706
• 关键词: AKT Signaling Pathway; Address; Adenylate Cyclase; Affect; Area; Arrestin; 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; human RGS2 protein; 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(申请人提供)：这项研究的目标是研究调控哺乳动物卵母细胞减数分裂进程的信号事件。未成熟的卵母细胞在第一阶段受阻，随着作用于卵泡细胞的黄体生成素的激增，它们重新进入减数分裂并成熟为卵子。黄体生成素将信号从卵泡细胞传递到卵母细胞的机制(S)尚不清楚。这项建议的目标1将研究黄体生成素启动小鼠卵母细胞减数分裂恢复的信号机制。在黄体生成素激增之前，减数分裂停止需要卵母细胞中高水平的cAMP；这种cAMP是由卵母细胞质膜中的G蛋白偶联受体GPR产生的，它刺激Gs激活腺苷酸环化酶。作为对黄体生成素的反应，卵母细胞中的cAMP水平下降，导致减数分裂恢复。在卵母细胞中，促黄体生成素的潜在作用靶点包括：1)GPR3，它可以通过激活G蛋白受体激酶(GRKs)和Li-arrestins而被关闭，这是下调大多数GPCRs的常见机制。2)Gs，其活性可被G蛋白信号转导(RGS)蛋白的调节剂抑制。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)缝隙连接层面的调控。这些途径将使用最近开发的显微注射封闭卵泡的卵母细胞的方法进行研究。目的2将通过检测人类卵母细胞是否含有与啮齿动物卵母细胞相同的信号通路，来检验人类卵母细胞减数分裂的停止和恢复是否依赖于与啮齿动物卵母细胞相同的途径。AIM 2还将描述通常发生在人类卵母细胞成熟过程中的细胞质事件。这些研究将提供关于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。如何调节减数分裂的问题与妇女健康问题高度相关。特别是，开发成功地使未成熟的人类卵母细胞在体外成熟的方法在临床上引起了极大的兴趣，这可能会导致体外受精治疗的改进，并提供比目前妇女更多的选择来保持她们的生育能力。改善体外成熟将需要了解减数分裂停止的所有阶段和调控卵母细胞成熟启动的生理机制。拟议的研究将有助于奠定这些临床进展的基础科学背景。