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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD028138-23
Application #
8452610
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
23
Fiscal Year
2013
Total Cost
$318,448
Indirect Cost
$116,137
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Min, Le; Soltis, Kathleen; Reis, Ana Claudia S et al. (2014) Dynamic kisspeptin receptor trafficking modulates kisspeptin-mediated calcium signaling. Mol Endocrinol 28:16-27
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
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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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