ROLE OF CIRCADIAN GENE EXPRESSION IN GNRH PULSATILITY

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The pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus is crucial for normal reproductive function in mammals, including humans. Although much past research has concentrated on what neuronal and hormonal factors may modulate this pulsatile release, the cellular and molecular mechanisms regulating the timing of these events has yet to be elucidated. Recent studies suggest that a transcriptional feedback loop may be responsive for conferring circadian oscillations of gene expression found in multiple cell types. It is as yet unclear, however, whether circadian genes may also influence GnRH gene expression or secretion. Given this, we will investigate the role of the circadian genes mper1, mper2 and clock on GnRH gene expression and secretion in vitro using GT1 cells and in vivo using transgenic mice, as outlined in the following specific aims: Specific Aim 1 Determine whether GT1 cells can be induced to express a circadian pattern of mper1 expression, and whether any changes in transcription of mper1 are associated with the synchronization of GnRH gene expression and/or peptide secretion. Specific Aim 2 Determine whether disruption of normal CLOCK signaling in Vitro in GT1 cells, and in vivo in transgenic mice, affects patterns and timing of GnRH gene expression and/or GnRH release. Results from these studies will allow for a greater understanding of possible molecular and cellular mechanisms underlying the pulsatile secretion of GnRH required for normal reproductive function.