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

基本信息

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
项目类别：
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&apos s Health Work base desensitization egg falls human RGS2 protein improved interest oocyte maturation phosphoric diester hydrolase programs response

项目摘要

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调节哺乳动物卵母细胞减数分裂进展的信号事件。未成熟的卵母细胞在 I 前期停滞，并响应作用于卵泡细胞的黄体生成素 LH 的激增，它们重新进入减数分裂并成熟为卵子。 LH 将信号从卵泡细胞传递到卵母细胞的机制尚不清楚。该提案的目标 1 将检查 LH 在小鼠卵母细胞中启动减数分裂恢复的信号机制。在 LH 激增之前，减数分裂停滞需要卵母细胞中 cAMP 水平较高；这种 cAMP 由卵母细胞质膜中的 G 蛋白偶联受体 GPRS 产生，刺激 Gs 激活腺苷酸环化酶。为了响应 LH，卵母细胞中的 cAMP 水平下降，导致减数分裂恢复。 LH 在卵母细胞中发挥作用的潜在靶点包括：1) GPR3，它可以通过激活 G 蛋白受体激酶 (GRK) 和 li-arrestins 来关闭，li-arrestins 是下调大多数 GPCR 的常见机制。 2）Gs，其活性可被G蛋白信号传导（RGS）蛋白的调节因子抑制。 3) AKT/PKB信号通路，已被证明可以影响多种物种减数分裂的恢复。 4）间隙连接水平的调节。将使用最近开发的显微注射卵泡封闭卵母细胞的方法来研究这些途径。目标 2 将通过检查人类卵母细胞是否含有这些信号传导途径的相同成分来检查人类卵母细胞减数分裂的停滞和恢复是否依赖于与啮齿动物卵母细胞相同的途径。目标 2 还将表征人类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。减数分裂如何调控的问题与女性健康问题高度相关。特别是，开发在体外成功成熟未成熟人类卵母细胞的方法在临床上引起了高度关注，这可能会导致体外受精治疗的改进，并为女性提供比目前更多的选择来保留其生育能力。体外成熟的改进需要了解减数分裂停滞的所有阶段以及调节卵母细胞成熟起始的生理机制。拟议的研究将有助于奠定此类临床进展的基础科学背景。