The goal of the Center for Reproductive Science and Medicine at UCSD is to develop understanding of the mechanisms that govern normal and disordered function of the hypothalamic-pituitary-ovarian axis. This application represents our renewal for years 29-33. Our productivity has been outstanding with 60 papers published and 9 submitted in 3 years of a 4-year award. We will 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 3 integrated, innovative Research Projects, all with experienced, internationally renowned leaders. Project I (Pamela L. Mellon, PL) will address the hormonal control of the pituitary gonadotrope, focusing on regulation by activin, GnRH, and steroid hormones in vitro and in vivo. The emphasis will be on understanding the synergy and interdependence between these hormones in controlling transcription in model immortalized gonadotrope cells, genetically modified mice, and mouse models of precocious puberty and PCOS. Project II (Jerrold M. Olefsky, PL) will chart new territory in the role of metabolic control in fertility. A dual in vivo/in vitro approach will elucidate the mechanisms of adiponectin, SirT1, and PPARy actions in regulating reproduction, using immortalized hypothalamic GnRH-secreting neurons and gonadotrope cells, novel genetically modified mice, and mouse models of PCOS. Project III (R. Jeffrey Chang, PL) will delineate the relative roles of specific factors implicated in excess production of androgen by the ovarian theca cell in women with PCOS and undertake studies in human ovary culture systems, addressing fundamental mechanisms underlying PCOS. All Project Leaders serve as Co-l's on other components of the Center and all 3 projects include teams of very experienced investigators. The Projects are highly interactive and synergistic, creating a coherent mechanistic and translational Center. The Administrative Core supports the Center, provides the Enrichment Program, and facilitates interactions within the Center and the SCCPIR Program. The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide.

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 pituitary function, metabolic abnormalities (insulin resistance/obesity), androgen excess, and anovulation. Our Center proposes an integrated program of three projects that address each aspect of PCOS: 1) pituitary hormone regulation, 2) metabolic control of fertility and 3) production of androgens. Studies include women and mouse models of human disease.

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 #
5U54HD012303-33
Application #
8446129
Study Section
Special Emphasis Panel (ZHD1-DSR-L (54))
Program Officer
De Paolo, Louis V
Project Start
1997-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
33
Fiscal Year
2013
Total Cost
$1,375,256
Indirect Cost
$485,122
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
Stephens, Shannon B Z; Chahal, Navdeep; Munaganuru, Nagambika et al. (2016) Estrogen Stimulation of Kiss1 Expression in the Medial Amygdala Involves Estrogen Receptor-α But Not Estrogen Receptor-β. Endocrinology 157:4021-4031
Kelley, Scott T; Skarra, Danalea V; Rivera, Alissa J et al. (2016) The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome. PLoS One 11:e0146509
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Baeza-Raja, Bernat; Sachs, Benjamin D; Li, Pingping et al. (2016) p75 Neurotrophin Receptor Regulates Energy Balance in Obesity. Cell Rep 14:255-68
Tolson, Kristen P; Garcia, Christian; Delgado, Iris et al. (2016) Metabolism and Energy Expenditure, But Not Feeding or Glucose Tolerance, Are Impaired in Young Kiss1r KO Female Mice. Endocrinology 157:4192-4199
Cho, Chang Gun; Pak, Kwang; Webster, Nicholas et al. (2016) Both canonical and non-canonical NF-κB activation contribute to the proliferative response of the middle ear mucosa during bacterial infection. Innate Immun :
Xie, Huimin; Hoffmann, Hanne M; Meadows, Jason D et al. (2015) Homeodomain Proteins SIX3 and SIX6 Regulate Gonadotrope-specific Genes During Pituitary Development. Mol Endocrinol 29:842-55

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