PROJECT II (Kl: SEMINARA) Over the last five years, Project II has explored the physiology of kisspeptin as a powerful stimulus of GnRH secretion. The focus of Project II in the current grant cycle is the integration of kisspeptin with another neuropeptide that has recently been implicated in the genetics of GnRH deficiency, neurokinin B. Patients with mutations in the neurokinin pathway have high rates of reversal of their hypogonadotropism with restoration of endogenous GnRH-induced LH pulses. The first specific aim explores the subphenotype of reversible GnRH deficiency in patients with mutations in the kisspeptin and neurokinin B pathways, and in particular, the relationship between reversal and sex steroid exposure. The second specific aim explores the physiologic interplay between kisspeptin and neurokinin B in stimulating GnRH secretion in normal volunteers and patients carrying mutations in each of these signaling pathways. These tools will include continuous kisspeptin administration via infusion-(acting as a surrogate kisspeptin receptor antagonist), and a neurokinin B receptor antagonist. The third specific aim extends the physiologic tools used in the human into the mouse, as well as incorporating phenotyping of mice with targeted deletions within the neurokinin B pathway, and developing a mouse model of reversible hypogonadotropism.
These studies have direct implications for reproductive medicine. Kisspeptin and neurokinin B (or analogous compounds) may provide another avenue treating patients reproductive disorders ranging form abnormalities of pubertal timing, to reproductive cancers, to endometriosis, and infertility.
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|Thompson, Iain R; Kaiser, Ursula B (2014) GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. Mol Cell Endocrinol 385:28-35|
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|Salian-Mehta, S; Xu, M; Knox, A J et al. (2014) Functional consequences of AXL sequence variants in hypogonadotropic hypogonadism. J Clin Endocrinol Metab 99:1452-60|
|Kaiser, Ursula B (2014) Editorial: advances in neuroscience: the BRAIN initiative and implications for neuroendocrinology. Mol Endocrinol 28:1589-91|
|Macedo, Delanie B; Abreu, Ana Paula; Reis, Ana Claudia S et al. (2014) Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab 99:E1097-103|
|Beneduzzi, Daiane; Trarbach, Ericka B; Min, Le et al. (2014) Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. Fertil Steril 102:838-846.e2|
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