The objective of our Center is to promote scientific excellence in translational science via well-designed studies of human germ cell development, based on a foundation of knowledge in model systems, and culminating with applications that address critical clinical need. To accomplish our objective, we propose three projects, a pilot project, and four cores. We also present several opportunities for a translational pilot project. The projects are: Project I) Germ Cell Differentiation from Human iPSCs and hESCs (Reijo Pera);Project 2) Translational Regulation of Meiotic Cell Cycle Onset and Progression in the Male (Fuller);Project 3) Derivation of Mature Human Oocytes from Primordial Follicles (Hsueh);and Pilot Project) Regulation of Translational Control in the Oocyte to Embryo Transition (Yao). We also present a translational pilot project for future consideration on primary ovarian insufficiency. Supporting the research are four cores: A) Administration;B) Outreach and Education;C) Microanalysis, Sequencing and Informatics;D) Reproductive Database. This application is a culmination of our reorganization and planning over the last several years and presents our vision for Reproductive and Stem Cell Biology based on outstanding basic and translational science. The application is put forth by a collaborative team that shares common interests in terms of genes and germ cell differentiation and maturation, pathways, developmental systems and overall educational, outreach and research goals. Each project consists of a strong basic component;in addition, three of the five projects and pilots have an equally-strong clinical component encompassing genetic analysis of human germ cell development from pluripotent stem cells to probe fundamental aspects and potential therapies, deriving mature oocytes to remedy primary ovarian insufficiency, and establishing the first registry of women with POI. Each project is relevant to the health of infertile women and men and each is informed by the elegant genetic systems of Drosophila and the mouse. The central theme of our Center is novel, forward-looking and built on a firm foundation of scientific and clinical inquiry with an innovative outreach and educational component with hopes of reaching out to other scientists, healthcare professionals.

Public Health Relevance

Our central theme is that human infertility, associated with few or no germ cells (oocytes or sperm) can be understood via translation of studies from model systems to human biology and can be alleviated by applying principle findings to the clinic. By adhering to the principles of our central theme, we will have an increased ability to define the origins and biological consequences of human infertility and may be able to alleviate common barriers to reproduction in infertile men and women, such as production of few germ cells.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-L (32))
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De Paolo, Louis V
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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Durruthy Durruthy, Jens; Ramathal, Cyril; Sukhwani, Meena et al. (2014) Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules. Hum Mol Genet 23:3071-84
Dominguez, Antonia A; Chiang, H Rosaria; Sukhwani, Meena et al. (2014) Human germ cell formation in xenotransplants of induced pluripotent stem cells carrying X chromosome aneuploidies. Sci Rep 4:6432
Ramathal, Cyril; Durruthy-Durruthy, Jens; Sukhwani, Meena et al. (2014) Fate of iPSCs derived from azoospermic and fertile men following xenotransplantation to murine seminiferous tubules. Cell Rep 7:1284-97
Durruthy-Durruthy, Jens; Briggs, Sharon F; Awe, Jason et al. (2014) Rapid and efficient conversion of integration-free human induced pluripotent stem cells to GMP-grade culture conditions. PLoS One 9:e94231
Reddy, Pradeep; Deguchi, Masashi; Cheng, Yuan et al. (2013) Actin cytoskeleton regulates Hippo signaling. PLoS One 8:e73763
Pera, Renee A Reijo (2013) Status of human germ cell differentiation from pluripotent stem cells. Reprod Fertil Dev 25:396-404
Medrano, Jose V; Pera, Renee A Reijo; Simon, Carlos (2013) Germ cell differentiation from pluripotent cells. Semin Reprod Med 31:14-23
Kawamura, Kazuhiro; Cheng, Yuan; Suzuki, Nao et al. (2013) Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci U S A 110:17474-9
Hsueh, Aaron J; Rauch, Rami (2012) Ovarian Kaleidoscope database: ten years and beyond. Biol Reprod 86:192
Cheng, Yuan; Kawamura, Kazuhiro; Deguchi, Masashi et al. (2012) Intraovarian thrombin and activated protein C signaling system regulates steroidogenesis during the periovulatory period. Mol Endocrinol 26:331-40

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