Genetics and Proteomics of Mouse Egg Activation
Genetics and Proteomics of Mouse Egg Activation
批准号:
10209649
负责人:
John C Schimenti
金额:
$19.45万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-03-15 至 2023-02-28
关键词:
AffectAnimalsAssisted Reproductive TechnologyBiochemicalBiological MarkersBiological ModelsCalciumCalcium SignalingCell CycleCell Differentiation processCell NucleusCellsChemicalsDataDepositionDetectionDevelopmentDiagnosisDiagnosticDiseaseDrosophila genusEmbryoEmbryonic DevelopmentEnzymesEventFailureFertilityFertilizationFertilization in VitroFutureGene ExpressionGene ProteinsGeneticGenetic TranscriptionGenetic studyGenomeHumanInfertilityInvertebratesIonophoresMammalsMaternal Messenger RNAMediatingMeiosisMembraneMetaphaseMethodologyModelingModificationMolecularMolecular GeneticsMonitorMusNatureNucleic AcidsOocytesOogenesisOrganismPathway interactionsPhosphorylationPhosphotransferasesPlacentaPost-Translational Protein ProcessingProceduresProcessProductionProtein IsoformsProteinsProteomeProteomicsRanaReportingRoleSea UrchinsSterilityStrontiumTestingTotipotentTranslationsanalytical toolbasecalmodulin-dependent protein kinase IIeggfemale fertilitymacromoleculemenphosphoproteomicsprotein expressionsperm celltooltranscriptometranslation factorzygote
中文摘要
项目摘要/摘要
人类和小鼠的排卵卵母细胞在减数分裂II期停滞。它们在转录上处于静止状态,但
母体携带的转录组和蛋白质组。受精触发“卵子激活”,卵子数量上升(S)
卵母细胞中的钙诱导了几个关键事件,使过渡到胚胎发育,即,
减数分裂的恢复和完成,卵子蛋白质组的变化,以及第一次减数分裂后的基因组激活
合子组织。因此,卵母细胞需要激活卵子才能成为全能受精卵。尽管
这一过程的本质对于女性生育来说,卵子激活的分子事件并不是很好
理解,主要是出于技术原因。鸡蛋的激活不需要新的转录;因此,核酸-
“基于”的组学比较不能提供信息。传递钙信号的大分子作用于
下游的细胞事件在人类或任何其他哺乳动物中都是未知的。
MW实验室最近的研究利用了果蝇模型系统的技术优势来表明
在卵子激活期间,母体提供的蛋白质组有很大的磷酸调节(这种情况也会发生
在青蛙和海胆中)。我们假设,我们的基因数据支持,这种翻译后
修饰调节储存的蛋白质的活性,以允许受阻的成熟卵母细胞转变为细胞
可以进行胚胎发育的。然后我们展示了一种钙调节的磷酸调节酶
调节细胞周期机制、翻译因子和其他所需蛋白质中的这些磷酸化变化
将卵子转化为胚胎。
在R21中,我们建议以小鼠为模型,对哺乳动物卵母细胞测试这一模型。跟随
程序类似于用于果蝇的程序,我们将确定是否存在磷酸蛋白质组
在小鼠卵子激活过程中的变化,以及哪些蛋白质经历这些变化。然后我们将测试一下
CaMKII,一种钙调节的激酶,已被证明是小鼠卵子激活所必需的,在
这些磷酸化变化。
我们的研究结果将在几个方面为该领域奠定基础,包括开发
小鼠卵母细胞的磷酸蛋白质组学及卵子中磷酸调节蛋白的确定
激活。研究结果将为未来研究受规制者的作用提供必要的信息
我们在这里确定的蛋白质,以及在这一关键发育过程中特定的磷酸调节的影响
过渡。这些基础研究对于确定人类的分子和遗传基础将是重要的。
与缺陷卵子激活相关的不育症,提供了监测这一过程的生物标记物,以及
有可能优化辅助生殖技术的条件。
英文摘要
PROJECT SUMMARY/ABSTRACT
Ovulated human and mouse oocytes are stalled in meiosis II. They are transcriptionally quiescent but have
a maternally-loaded transcriptome and proteome. Fertilization triggers “egg activation”, in which a rise(s) of
calcium in the oocyte induces several key events that allow transition to embryonic development, namely,
meiotic resumption and completion, changes to the egg’s proteome, and genome activation after the first
zygotic division. Therefore, egg activation is required for the oocyte to become a totipotent zygote. Despite the
essential nature of this process for female fertility, the molecular events of egg activation are not well
understood, primarily for technical reasons. Egg activation occurs without new transcription; thus nucleic acids-
based ‘omics comparisons are uninformative. The macromolecules that transduce the calcium signal to effect
downstream cellular events are not known in humans or any other mammal.
Recent studies in MW’s lab exploited technical advantages of the Drosophila model system to show that
there is large phospho-modulation of the maternally-provided proteome during egg activation (this also occurs
in frogs and sea urchins). We hypothesized, and our genetic data supported, that this posttranslational
modification regulated the activity of stored proteins to permit transition of an arrested mature oocyte to a cell
that can undertake embryogenesis. We then showed that a calcium-regulated phospho-regulatory enzyme
mediates these phospho-changes in the cell cycle machinery, translation factors and other proteins needed to
transition the egg to an embryo.
In this R21 we propose to test this model for mammalian oocytes, using mouse as a model. Following
procedures analogous to those used for Drosophila, we will determine whether there are phosphoproteome
changes during mouse egg activation, and which proteins undergo these changes. We will then test the role of
CamKII, a calcium-regulated kinase that has been shown to be required for egg activation in mouse, in making
these phospho-changes.
The results of our studies will lay the groundwork for the field in several ways, including developing
phosphoproteomics for mouse oocytes and determining proteins that are phospho-regulated during egg
activation. The results will provide information essential for future studies into the roles of the regulated
proteins that we identify here, and the effects of specific phosphomodulations during this critical developmental
transition. Such fundamental studies will be important for identifying the molecular and genetic bases of human
infertilities associated with defective egg activation, providing biomarkers to monitor this process, and
potentially for optimizing conditions for assisted reproductive technologies.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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海外基金