The goal of the Center for Reproductive Science and Medicine at UC San Diego is to develop understanding of the fundamental mechanisms that cause disordered function of the hypothalamic-pituitary-ovarian axis in Polycystic Ovary Syndrome (PCOS). This application represents our renewal for years 34-38. Our productivity has been exceptional with 176 papers published since the submission of our previous award. We continue to produce novel, significant contributions to the reproductive sciences, integrating multidisciplinary clinical, translational, and basic research to facilitate and accelerate the translation of promising new discoveries into clinical medicine. We are proposing three integrated, innovative Research Projects, all with experienced, internationally renowned leaders. The renewal of Project I (Pamela L. Mellon, PL) will address the roles of FSH transcriptional and secretory control in the dysregulation of the neuroendocrine system in mouse models of PCOS and premature ovarian failure. The focus will be on the roles of androgen excess, genetics, epigenetics, and specific single nucleotide polymorphisms in the FSH? gene associated with PCOS. Project II (Mark A. Lawson, PL), a new project, will chart novel territory in understanding the roles of fatty acids and excess androgens in regulating the hypothalamic GnRH pulse generator and GnRH sensitivity at the pituitary in PCOS. Using novel genetically modified mice, highly sensitive assays to measure LH pulses in vivo, mouse models of PCOS, perifusion cell culture models, high-fat diet, and lipid infusions, this Project investigates the roles of free fatty acids and androgens in dysregulation of the hypothalamic-pituitary-ovarian axis and their overall contribution to the PCOS phenotype. The renewal of Project III (R. Jeffrey Chang, PL) will delineate the role of androgens on follicle function implicated in anovulation in clinical studies in women with PCOS and address fundamental mechanisms underlying dysfolliculogenesis in PCOS using a mouse model overexpressing Cyp17. All three projects include teams of very experienced investigators and integrate basic and translational studies to address major aspects of the mechanisms of PCOS. The Projects are highly interactive and synergistic, creating a coherent, mechanistic, and translational research program. The 11 faculty involved in the Center are all at the La Jolla campus of UCSD, most have worked together for many years, and several are new young investigators that have been recruited to or mentored within the Center. The Administrative Core supports the Center, provides the Enrichment Programs, and facilitates interactions within the Center and the NCTRI Program. The new Education/Outreach Core is novel and exciting. Unique strengths of the Center include its translational accomplishments, outstanding faculty, long-term leadership, integration of clinical and basic research, cohesive collaboration, and location at UC San Diego in La Jolla.

Public Health Relevance

Polycystic ovary syndrome (PCOS) is the most common cause of female infertility, occurring in about 1 in 10 women of childbearing age. Hallmarks are disordered neuroendocrine function, metabolic abnormalities, obesity, androgen excess, and anovulation, but the etiology remains unknown. Our Center is an integrated program of three projects that address the fundamental mechanisms of PCOS utilizing clinical studies in women with PCOS, genetic approaches, cultured cell models, and mouse models of PCOS.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
5P50HD012303-37
Application #
9675108
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Moss, Stuart B
Project Start
1997-04-01
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
37
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ryan, Genevieve E; Malik, Shaddy; Mellon, Pamela L (2018) Antiandrogen Treatment Ameliorates Reproductive and Metabolic Phenotypes in the Letrozole-Induced Mouse Model of PCOS. Endocrinology 159:1734-1747
Torres, Pedro J; Siakowska, Martyna; Banaszewska, Beata et al. (2018) Gut Microbial Diversity in Women With Polycystic Ovary Syndrome Correlates With Hyperandrogenism. J Clin Endocrinol Metab 103:1502-1511
Hoffmann, Hanne M; Gong, Ping; Tamrazian, Anika et al. (2018) Transcriptional interaction between cFOS and the homeodomain-binding transcription factor VAX1 on the GnRH promoter controls Gnrh1 expression levels in a GnRH neuron maturation specific manner. Mol Cell Endocrinol 461:143-154
Belli, Martina; Shimasaki, Shunichi (2018) Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function. Vitam Horm 107:317-348
Yang, Jennifer A; Hughes, Jessica K; Parra, Ruby A et al. (2018) Stress rapidly suppresses in vivo LH pulses and increases activation of RFRP-3 neurons in male mice J Endocrinol 239:339-350
Hoffmann, Hanne; Pandolfi, Erica; Larder, Rachel et al. (2018) Haploinsufficiency of Homeodomain Proteins Six3, Vax1, and Otx2, Causes Subfertility in Mice Via Distinct Mechanisms. Neuroendocrinology :
Belli, Martina; Iwata, Nahoko; Nakamura, Tomoko et al. (2018) FOXL2C134W-Induced CYP19 Expression via Cooperation With SMAD3 in HGrC1 Cells. Endocrinology 159:1690-1703
Que, Xuchu; Hung, Ming-Yow; Yeang, Calvin et al. (2018) Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice. Nature 558:301-306
Acevedo-Rodriguez, A; Kauffman, A S; Cherrington, B D et al. (2018) Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling. J Neuroendocrinol 30:e12590
Li, Song; Mbong, Ekaette F; John, Denise T et al. (2018) Induction of Stress Signaling In Vitro and Suppression of Gonadotropin Secretion by Free Fatty Acids in Female Mouse Gonadotropes. Endocrinology 159:1074-1087

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