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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD055764-07
Application #
8435286
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
7
Fiscal Year
2013
Total Cost
$308,929
Indirect Cost
$108,975
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Bianco, Katherine; Gormley, Matthew; Farrell, Jason et al. (2016) Placental transcriptomes in the common aneuploidies reveal critical regions on the trisomic chromosomes and genome-wide effects. Prenat Diagn 36:812-22
Tran, Nam D; Kissner, Michael; Subramanyam, Deepa et al. (2016) A miR-372/let-7 Axis Regulates Human Germ Versus Somatic Cell Fates. Stem Cells 34:1985-91
Krishnakumar, Raga; Chen, Amy F; Pantovich, Marisol G et al. (2016) FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity. Cell Stem Cell 18:104-17
Maltepe, Emin; Fisher, Susan J (2015) Placenta: the forgotten organ. Annu Rev Cell Dev Biol 31:523-52
Parchem, Ronald J; Moore, Nicole; Fish, Jennifer L et al. (2015) miR-302 Is Required for Timing of Neural Differentiation, Neural Tube Closure, and Embryonic Viability. Cell Rep 12:760-73
Guzman-Ayala, Marcela; Sachs, Michael; Koh, Fong Ming et al. (2015) Chd1 is essential for the high transcriptional output and rapid growth of the mouse epiblast. Development 142:118-27
Piltonen, T T; Chen, J C; Khatun, M et al. (2015) Endometrial stromal fibroblasts from women with polycystic ovary syndrome have impaired progesterone-mediated decidualization, aberrant cytokine profiles and promote enhanced immune cell migration in vitro. Hum Reprod 30:1203-15
Smith-McCune, Karen; Chen, Joseph C; Greenblatt, Ruth M et al. (2015) Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: A Randomized Crossover Study. PLoS One 10:e0129769
Rahmioglu, Nilufer; Fassbender, Amelie; Vitonis, Allison F et al. (2014) World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: III. Fluid biospecimen collection, processing, and storage in endometriosis research. Fertil Steril 102:1233-43
Fassbender, Amelie; Rahmioglu, Nilufer; Vitonis, Allison F et al. (2014) World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: IV. Tissue collection, processing, and storage in endometriosis research. Fertil Steril 102:1244-53

Showing the most recent 10 out of 73 publications