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.
With this proposal we will study the mechanisms involved in oocyte developmental competence Understanding this process at the molecular level will provide new tools and open new strategies to diagnose the origin of infertility and improve treatments of this condition. It will also provide new biomarkers useful to predict oocyte quality during in vitro fertilization.
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