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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Blondel, Olivier
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
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Ruf-Zamojski, Frederique; Fribourg, Miguel; Ge, Yongchao et al. (2018) Regulatory Architecture of the L?T2 Gonadotrope Cell Underlying the Response to Gonadotropin-Releasing Hormone. Front Endocrinol (Lausanne) 9:34
Fribourg, Miguel; Logothetis, Diomedes E; González-Maeso, Javier et al. (2017) Elucidation of molecular kinetic schemes from macroscopic traces using system identification. PLoS Comput Biol 13:e1005376
Stern, Estee; Ruf-Zamojski, Frederique; Zalepa-King, Lisa et al. (2017) Modeling and high-throughput experimental data uncover the mechanisms underlying Fshb gene sensitivity to gonadotropin-releasing hormone pulse frequency. J Biol Chem 292:9815-9829
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 ?-subunit (FSH?) gene expression. J Biol Chem 289:16164-75
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
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; Zaslavsky, Elena et al. (2013) ?-catenin regulates GnRH-induced FSH? 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

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