The proposal is aimed at gaining new insight into the developmental processes that underlie the maturation of the reproductive hypothalamus and, hence, the onset of female puberty. Utilizing the rat as the animal model, experiments are proposed to examine the hypothesis that brain neuronotrophic factors regulate the development of the hypothalamic LHRH- secreting system, which culminates when a discharge of LHRH release triggers the first preovulatory surge of gonadotropins. To this end, the following specific aims are proposed. 1. To document the hypothesis that nerve growth factor (NGF) and transforming growth factor alpha (TGFalpha), as well as their respective receptors, are expressed in the hypothalamus, and to examine their contribution to the developmental regulation of LHRH secretion. 2. To examine the hypothesis that TGFalpha facilitates the morphological and functional differentiation of LHRH neurons and to determine whether NGF is trophic for LHRH neurons and/or a neuronal system regulatory to LHRH function. 3. To examine the hypothesis that hypothalamic trophic factors, and in particular the epidermal growth factor receptor EGFr/TGFalpha ligand system can influence LHRH synthesis by directly regulating transcriptional activity of the LHRH gene. 4. To examine the hypothesis that TGFalpha is one of the neuronotrophic factors that contribute to the peripubertal, gonadal-independent activation of LHRH release. The accomplishment of these aims depends on the team participation of one neuroendocrinologist, one molecular biologist, and two morphologists, and on the integrated use of neuroendocrine, neurobiology and molecular biology approaches.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD025123-04
Application #
3326063
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1990-09-01
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Oregon Regional Primate Research Center
Department
Type
DUNS #
City
Beaverton
State
OR
Country
United States
Zip Code
97006
Lomniczi, Alejandro; Loche, Alberto; Castellano, Juan Manuel et al. (2013) Epigenetic control of female puberty. Nat Neurosci 16:281-9
Lomniczi, Alejandro; Wright, Hollis; Castellano, Juan Manuel et al. (2013) A system biology approach to identify regulatory pathways underlying the neuroendocrine control of female puberty in rats and nonhuman primates. Horm Behav 64:175-86
Dissen, G A; Lomniczi, A; Boudreau, R L et al. (2012) Targeted gene silencing to induce permanent sterility. Reprod Domest Anim 47 Suppl 4:228-32
Sandau, Ursula S; Alderman, Zefora; Corfas, Gabriel et al. (2012) Astrocyte-specific disruption of SynCAM1 signaling results in ADHD-like behavioral manifestations. PLoS One 7:e36424
Dissen, Gregory A; Lomniczi, Alejandro; Heger, Sabine et al. (2012) Hypothalamic EAP1 (enhanced at puberty 1) is required for menstrual cyclicity in nonhuman primates. Endocrinology 153:350-61
Matagne, V; Kim, J G; Ryu, B J et al. (2012) Thyroid transcription factor 1, a homeodomain containing transcription factor, contributes to regulating periodic oscillations in GnRH gene expression. J Neuroendocrinol 24:916-29
Mueller, Johanna K; Koch, Ines; Lomniczi, Alejandro et al. (2012) Transcription of the human EAP1 gene is regulated by upstream components of a puberty-controlling Tumor Suppressor Gene network. Mol Cell Endocrinol 351:184-98
Sandau, Ursula S; Mungenast, Alison E; McCarthy, Jack et al. (2011) The synaptic cell adhesion molecule, SynCAM1, mediates astrocyte-to-astrocyte and astrocyte-to-GnRH neuron adhesiveness in the mouse hypothalamus. Endocrinology 152:2353-63
Yeung, Kay T; Das, Sharmistha; Zhang, Jin et al. (2011) A novel transcription complex that selectively modulates apoptosis of breast cancer cells through regulation of FASTKD2. Mol Cell Biol 31:2287-98
Sandau, Ursula S; Mungenast, Alison E; Alderman, Zefora et al. (2011) SynCAM1, a synaptic adhesion molecule, is expressed in astrocytes and contributes to erbB4 receptor-mediated control of female sexual development. Endocrinology 152:2364-76

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