Modulation of gonadotrope signaling by GnRH and its analogs is central to the treatment of a wide spectrum of diseases, including infertility and gonadal hormone-dependent tumors. During normal reproductive function, the gonadotrope interprets the pattern of GnRH and other extracellular stimuli in order to properly regulate gonadotropin biosynthesis. During the previous funding period, we have developed and applied multivariate systems biology assay, data acquisition and simulation techniques in order to understand the function of the gonadotrope as a molecular data processing network. We have developed high throughput quantitative genomics techniques and studied the global transcriptional program modulated by GnRH, the connections between signaling pathways and the transcriptome, the frequency dependence of continuous modular differential equation models and the characteristics of gonadotrope signal processing at the single cell level. We now propose the following aims that will generate a comprehensive model of gonadotrope molecular behavior in response to physiologically relevant inputs such as pulsed GnRH. 1 Experimentally refine the topological map of the gonadotrope signaling and gene network and develop a community-directed, pathway-based gonadotrope signaling map and knowledgebase. 2) Develop a scalable superfusion instrument to study large numbers of samples and single cell signaling/gene responses to GnRH frequency and its modulation by multiple stimuli and develop mathematical representations to test hypotheses about gonadotrope signal processing and frequency decoding. We will elucidate the mechanism of the GnRH frequency response and integration with other inputs and provide a solid basis for predictive mathematical modeling. These studies will provide fundamental insight into the mechanisms used by the gonadotrope's signaling network to control biosynthesis.

Public Health Relevance

The treatment of many medical conditions, including infertility and reproductive system cancers, involves effects at the gonadotrope cell in the pituitary gland. The goal of this research is to generate detailed datasets and predictive models of these cells to help improve the treatment of these conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046943-18
Application #
8308563
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Blondel, Olivier
Project Start
1993-09-01
Project End
2013-04-30
Budget Start
2012-02-01
Budget End
2013-04-30
Support Year
18
Fiscal Year
2012
Total Cost
$390,894
Indirect Cost
$129,676
Name
Icahn School of Medicine at Mount Sinai
Department
Neurology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Choi, Soon Gang; Wang, Qian; Jia, Jingjing et al. (2016) Characterization of Gonadotrope Secretoproteome Identifies Neurosecretory Protein VGF-derived Peptide Suppression of Follicle-stimulating Hormone Gene Expression. J Biol Chem 291:21322-21334
Choi, Soon Gang; Wang, Qian; Jia, Jingjing et al. (2014) Growth differentiation factor 9 (GDF9) forms an incoherent feed-forward loop modulating follicle-stimulating hormone β-subunit (FSHβ) gene expression. J Biol Chem 289:16164-75
Pincas, Hanna; Choi, Soon Gang; Wang, Qian et al. (2014) Outside the box signaling: secreted factors modulate GnRH receptor-mediated gonadotropin regulation. Mol Cell Endocrinol 385:56-61
Wang, Qian; Chikina, Maria D; Pincas, Hanna et al. (2014) Homer1 alternative splicing is regulated by gonadotropin-releasing hormone and modulates gonadotropin gene expression. Mol Cell Biol 34:1747-56
Wang, Qian; Chikina, Maria; Zaslavsky, Elena et al. (2013) β-catenin regulates GnRH-induced FSHβ gene expression. Mol Endocrinol 27:224-37
Choi, Soon-Gang; Jia, Jingjing; Pfeffer, Robert L et al. (2012) G proteins and autocrine signaling differentially regulate gonadotropin subunit expression in pituitary gonadotrope. J Biol Chem 287:21550-60
Yuen, Tony; Choi, Soon Gang; Pincas, Hanna et al. (2012) Optimized amplification and single-cell analysis identify GnRH-mediated activation of Rap1b in primary rat gonadotropes. Mol Cell Endocrinol 350:10-9
Choi, Soon Gang; Ruf-Zamojski, Frederique; Pincas, Hanna et al. (2011) Characterization of a MAPK scaffolding protein logic gate in gonadotropes. Mol Endocrinol 25:1027-39
Sealfon, Stuart C; Chu, Tearina T (2011) RNA and DNA microarrays. Methods Mol Biol 671:3-34
Fink, Marc Y; Pincas, Hanna; Choi, Soon Gang et al. (2010) Research resource: Gonadotropin-releasing hormone receptor-mediated signaling network in LbetaT2 cells: a pathway-based web-accessible knowledgebase. Mol Endocrinol 24:1863-71

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