Mechanisms Controlling Oocyte Developmental Competence and Embryo

控制卵母细胞发育能力和胚胎的机制

基本信息

批准号：
8286510
负责人：
Marco Conti
金额：
$ 32.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8286510
关键词：
Affect Amphiregulin Animal Model Assisted Reproductive Technology Biological Biological Assay Biological Markers Cell Communication Cell Cycle Chromatin Remodeling Factor Code Collaborations Competence Data Data Analyses Development Diagnosis EGF gene Embryo Embryonic Development Environment Failure Female infertility Fertilization Fertilization in Vitro Genetic Models Genetic Transcription Genetic Translation Genome Germ Cells Human In Vitro Infertility Instruction Knockout Mice Laboratories Lead Maternal Messenger RNA Measurement Meiosis Messenger RNA Methods Modeling Molecular Monitor Mus Nature Oocytes Patients Pattern Play Process Protein Secretion Proteins Regulation Reporter Research Resolution Rodent Role Scientist Signal Transduction Somatic Cell Students Testing Time Transcript Translating Translational Regulation Translations Work assisted reproduction base chromatin remodeling clinical practice endometriosis genome-wide genome-wide analysis global environment high school human female improved in vitro Model in vivo nuclear reprogramming oocyte maturation programs research study tool zygote

项目摘要

PROJECT SUMMARY (See instructions): PROJECT I The overarching hypothesis that we will test with this proposal is that human female infertility and assisted reproductive technology (ART) failures are, in part, caused by a disruption of the maternal mRNA translational program. Using a genome-wide strategy, we have assembled a blueprint of the translational regulations active during mouse oocyte maturation. We demonstrated that a large number of mRNAs coding for cell cycle components and for components of the transcriptional and chromatin remodeling machinery are translated following a well defined succession early during oocyte maturation. These findings have led to the hypothesis that timed translation of a subset of maternal mRNAs is critical for the oocyte to develop as an embryo. Moreover, we propose that somatic cell signals control this translational program of the oocyte. On the basis of preliminary data showing that the EGF-network plays a role in these somatic-germ cell interactions, we will explore how these signals contribute to developmental competence. The experimental plan is organized along three specific aims. With the first Aim, the oocyte translation program will be characterized in in vivo genetic models of compromised competence or after in vitro maturation. In the second Aim, the mechanisms by which somatic cells regulate translation in the oocytes will be investigated using in vitro models where somatic germ cell interactions are maintained and with reporters monitoring translation of candidate transcripts. The third Aim will focus on translation of mRNAs coding for oocyte secretory products to predict actual protein secretion. These measurements will be used as a readout of correct execution of the translational program. Secretion from human oocytes will be used for proof of principle that these patterns reflect the competence of the oocyte to sustain embryo development. The concepts developed with this project will open new avenues for monitoring oocyte quality in assisted reproduction in clinical practice.

项目摘要（参见说明）：项目 I 我们将通过该提案测试的总体假设是，人类女性不孕和辅助生殖技术 (ART) 失败部分是由母体 mRNA 翻译程序的破坏引起的。使用全基因组策略，我们构建了小鼠卵母细胞成熟过程中活跃的翻译调控的蓝图。我们证明大量的 mRNA 编码细胞周期成分以及转录和染色质重塑机制的成分在卵母细胞成熟早期按照明确的连续性进行翻译。这些发现引发了这样的假设：母体 mRNA 子集的定时翻译对于卵母细胞发育为胚胎至关重要。此外，我们提出体细胞信号控制卵母细胞的这种翻译程序。在初步数据表明 EGF 网络在这些体细胞-生殖细胞相互作用中发挥作用，我们将探讨这些信号如何促进发育能力。该实验计划是按照三个具体目标组织的。根据第一个目标，卵母细胞翻译程序将在能力受损的体内遗传模型或体外成熟后进行表征。在第二个目标中，将使用维持体生殖细胞相互作用的体外模型来研究体细胞调节卵母细胞翻译的机制，并用报告基因监测候选转录本的翻译。第三个目标将重点关注编码卵母细胞分泌产物的 mRNA 的翻译，以预测实际的蛋白质分泌。这些测量结果将用作翻译程序正确执行的读数。人类卵母细胞的分泌物将用于原理证明，这些模式反映了卵母细胞维持胚胎发育的能力。该项目开发的概念将为临床实践中辅助生殖中卵母细胞质量监测开辟新途径。