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Patrick Chappell
Assistant Professor, College of Veterinary Medicine
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RESEARCH:
My laboratory investigates the molecular and cellular mechanisms responsible for modulating gonadotropin-releasing hormone (GnRH) gene expression and neuropeptide secretion. This decapeptide mediates synthesis and release of the gonadotropin hormones from the pituitary, thus regulating critical physiological processes including ovulation and pubertal progression. In mammals, GnRH is released in a rhythmic, episodic pattern from the hypothalamus, and while this phenomenon is well documented, mechanisms underlying this pulsatile release remain elusive. Interestingly, while GnRH secretion patterns can be modulated by exogenous neural and hormonal signals, the mechanism underlying this "pulse generator" lies within these unique neurons, shown by in vitro studies using immortalized GT1 cell lines, a homogenous GnRH-secreting cell type capable of recapitulating rodent pulse release patterns in culture. My lab uses this hypothalamic cell line, in conjunction with multiple in vivo models, to examine multiple regulatory levels involved in GnRH pulse and surge generation.
To address what molecular program within GnRH neurons allows for the generation of discretely timed secretory patterns, we have incorporated insights from the field of circadian biology to construct molecular models of cellular timing mechanisms, to investigate how dynamic transcriptional changes can influence cell responsiveness and neurosecretion. We are currently investigating circadian clock influence on secretion at multiple regulatory levels, including GnRH gene expression, post-transcriptional and -translational peptide processing, and changes in membrane conductance, using cell culture, transgenic animal models, and calcium imaging, among others. Another major focus of the lab concentrates on the phenomenon of steroid positive feedback to elicit preovulatory gonadotropin surges; in particular, how ovarian steroids may act permissively for the transduction of circadian signals to influence GnRH expression and secretion.
This small but crucial population of neurons required for reproduction is flexible enough to integrate multiple neural and hormonal signals reflecting numerous environmental cues, and modulate secretion to ensure maximal adaptation, propagation, and thus survival. Insights into the underlying mechanisms of reproductive neurosecretion will aid in the treatment of multiple pathologies, including idiopathic hypogonadism and polycystic ovarian syndrome (PCOS).