Activation of the gonadotropin-releasing hormone (GnRH) receptor initiates a number of complex signaling cascades in pituitary gonadotropes. The rhythmic stimulation of gonadotropes by pulsatile GnRH underlies the differential control of luteinizing hormone and follicle-stimulating hormone production, and ultimately the control of reproduction. GnRH receptor signaling cascades regulate gonadotropin secretion, gene transcription and cell differentiation. We have shown that GnRH regulates protein synthesis and activates the unfolded protein response (UPR), a protective response to modulate stressful demands of protein synthesis. The UPR also activated by inflammatory and metabolic stress signals. The regulatory schemes utilized by the GnRH receptor are essential to maintain cell homeostasis and sensitivity to recurring GnRH pulses. To maintain pulse sensitivity and hormone synthesis, gonadotropes must resolve the intracellular alterations induced by secretion, increase protein synthesis to continue to meet these demands, and resolve the signaling events activated by the previous pulse to allow full response to the next. We have identified the UPR and control of translation as central elements maintaining gonadotrope sensitivity to GnRH and biosynthetic capacity. We propose to examine these components in vitro to determine their mechanism of regulation and in experimental mouse models to determine their physiological role in reproduction. The UPR may provide a direct link between physiological stress and reproductive function.
Specific Aim 1 : The Unfolded Protein Response in gonadotrope function. We will determine the role of the three main regulators of the unfolded protein response, EIF2AK3 and ERN1, in normal gonadotrope cell function Specific Aim 2: Mechanisms of mRNA redistribution in response to GnRH We have demonstrated that GnRH causes a redistribution of mRNA in gonadotropes. We will determine the specificity of redistribution and the factors determining susceptibility to redistribution.
Specific Aim 3 : Physiological consequences of an impaired stress response in mice We will examine the role of the unfolded protein response in normal gonadotrope cell function by examining the reproductive impact of pituitary-specific knockout of critical UPR regulatory factors.

Public Health Relevance

To preserve normal reproductive hormone production and to respond correctly to environmental cues, pituitary cells must minimize cellular stress and adapt to the demand of continued hormone production. We are investigating the mechanisms cells use to adapt to stress and preserve normal cell function. These regulatory pathways are essential to assure proper reproductive hormone synthesis and reproductive success.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037568-13
Application #
8495119
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
2000-03-20
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2013
Total Cost
$295,586
Indirect Cost
$104,268
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
Do, Minh-Ha T; Kim, Taeshin; He, Feng et al. (2014) Polyribosome and ribonucleoprotein complex redistribution of mRNA induced by GnRH involves both EIF2AK3 and MAPK signaling. Mol Cell Endocrinol 382:346-57
Kim, Taeshin; Do, Minh-Ha T; Lawson, Mark A (2014) Translational control of gene expression in the gonadotrope. Mol Cell Endocrinol 385:78-87
Chen, Buxin; Siderovski, David P; Neubig, Richard R et al. (2014) Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins. J Biol Chem 289:1580-91
Terasaka, Tomohiro; Otsuka, Fumio; Tsukamoto, Naoko et al. (2013) Mutual interaction of kisspeptin, estrogen and bone morphogenetic protein-4 activity in GnRH regulation by GT1-7 cells. Mol Cell Endocrinol 381:8-15
Lawson, Mark A (2013) Commentary: meeting the challenge to train the next generation of endocrinologists: filling, diversifying, and plugging leaks in the career pipeline. Endocrinology 154:2581-5
Takeda, Masaya; Otsuka, Fumio; Takahashi, Hiroaki et al. (2012) Interaction between gonadotropin-releasing hormone and bone morphogenetic protein-6 and -7 signaling in LýýT2 gonadotrope cells. Mol Cell Endocrinol 348:147-54
Mistry, Devendra S; Tsutsumi, Rie; Fernandez, Marina et al. (2011) Gonadotropin-releasing hormone pulse sensitivity of follicle-stimulating hormone-beta gene is mediated by differential expression of positive regulatory activator protein 1 factors and corepressors SKIL and TGIF1. Mol Endocrinol 25:1387-403
Nguyen, Kathryn A; Intriago, Rachel E; Upadhyay, Hiral C et al. (2010) Modulation of gonadotropin-releasing hormone-induced extracellular signal-regulated kinase activation by dual-specificity protein phosphatase 1 in LbetaT2 gonadotropes. Endocrinology 151:4882-93
Otani, Hiroyuki; Otsuka, Fumio; Takeda, Masaya et al. (2009) Regulation of GNRH production by estrogen and bone morphogenetic proteins in GT1-7 hypothalamic cells. J Endocrinol 203:87-97
Navratil, Amy M; Song, Hyunjin; Hernandez, Jeniffer B et al. (2009) Insulin augments gonadotropin-releasing hormone induction of translation in LbetaT2 cells. Mol Cell Endocrinol 311:47-54

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