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 #
5U54HD012303-30
Application #
7846887
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
2010-04-01
Budget End
2011-03-31
Support Year
30
Fiscal Year
2010
Total Cost
$1,433,052
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
Fernandez, Marina O; Hsueh, Katherine; Park, Hyun Tae et al. (2017) Astrocyte-Specific Deletion of Peroxisome-Proliferator Activated Receptor-? Impairs Glucose Metabolism and Estrous Cycling in Female Mice. J Endocr Soc 1:1332-1350
Fernandez, Marina O; Sharma, Shweta; Kim, Sun et al. (2017) Obese Neuronal PPAR? Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility. Endocrinology 158:121-133
Tang, Kechun; Pasqua, Teresa; Biswas, Angshuman et al. (2017) Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice. J Endocrinol 232:137-153
Takahashi, Nozomi; Harada, Miyuki; Hirota, Yasushi et al. (2017) Activation of Endoplasmic Reticulum Stress in Granulosa Cells from Patients with Polycystic Ovary Syndrome Contributes to Ovarian Fibrosis. Sci Rep 7:10824
Homer, Michael V; Rosencrantz, Marcus A; Shayya, Rana F et al. (2017) The effect of estradiol on granulosa cell responses to FSH in women with polycystic ovary syndrome. Reprod Biol Endocrinol 15:13
Yamada-Nomoto, Kaori; Yoshino, Osamu; Akiyama, Ikumi et al. (2017) PAI-1 in granulosa cells is suppressed directly by statin and indirectly by suppressing TGF-? and TNF-? in mononuclear cells by insulin-sensitizing drugs. Am J Reprod Immunol 78:
Hoffmann, Hanne M; Trang, Crystal; Gong, Ping et al. (2016) Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility. J Neurosci 36:3506-18
Baeza-Raja, Bernat; Sachs, Benjamin D; Li, Pingping et al. (2016) p75 Neurotrophin Receptor Regulates Energy Balance in Obesity. Cell Rep 14:255-68
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
Hoffmann, Hanne M; Mellon, Pamela L (2016) A small population of hypothalamic neurons govern fertility: the critical role of VAX1 in GnRH neuron development and fertility maintenance. Neurosci Commun (Houst) 2:

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