Circadian Regulation of Gonadotropin-Releasing Hormone

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DESCRIPTION (provided by applicant): Whereas it has long been known that normal mammalian reproduction depends upon the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, it is yet unclear what cellular and molecular mechanisms lie at the heart of this exceptionally timed pulse release. Additionally, while previous studies have implicated the 24-hour biological clock in the control of reproductive hormone secretion, it remains unknown how the circadian clock might modulate the amplitude or frequency of synchronous GnRH secretory release to regulate reproduction. Preliminary work in this laboratory demonstrates that not only are all molecular clock components expressed in the GnRH-secreting GT1-7 cell line, but that transcripts oscillate in these cultured cells with a circadian period. Strikingly, perturbation of the clock in perifused GT1-7 cells, via transient transfection of a dominant-negative Clock, disrupts normal secretory pulse patterns, showing that an intracellular circadian clock within GriRH neurons can modulate secretion. To investigate this further, the following proposal will 1) use in vitro and in vivo models to determine the necessity of a GnRH-specific molecular clock on patterns of release required for proper reproductive status, 2) examine potential intracellular mechanisms, including transcriptional regulation and properties of cell excitability, underlying circadian clock modulation of GnRH, and 3) explore the role of the suprachiasmatic nucleus (SCN), the brain's master clock, in influencing GnRH secretion, and the involvement of cell-specific molecular oscillators in this regulation. Results from this proposal have the potential to answer many fundamental questions regarding the nature of the GnRH "pulse generator", and how patterns of secretion may be altered by cell-cell communication to produce preovulatory surges. Additionally, these studies could provide insight into broader mechanisms of endocrine neurosecretion, and advance the field of circadian biology by demonstrating how transcriptional oscillations can control synchronous events at the multi-cellular and tissue level, in order to regulate numerous biological processes, from cellular metabolism to exocytosis, and even to orchestrate complex series of behaviors. Potential applications could lead to new directions in treating a range of physiological disorders that result from malfunction of hypothalamic reproductive neurosecretion, including polycystic ovarian syndrome and primary ideopathic hypogonadism.