Kisspeptin, neurokinin B, and dynorphin signaling provide essential guidance and stimulation to GnRH neurons. Though the past decade has seen extraordinary advances in our understanding of this signaling network, this grant employs novel assays and receptor agonist and antagonist administration in vivo to challenge several dogmas in reproductive endocrinology. These complementary approaches, performed in rhesus monkeys, healthy volunteers, and patients with reproductive disease, unite two investigators with experience in genetics, physiology, and pharmacology. This interdisciplinary collaboration is well positioned to attack the complexities of the hypothalamic architecture that regulates GnRH secretion. Thus, by translating fluidly between monkey and man, between juvenile and adult, and between physiology and pathophysiology, this grant aims to generate novel insights into sexual maturation and develop new treatments for patients with reproductive disorders.
This project focuses upon the kisspeptin-neurokininB-dynorphin (KNDy) hypothalamic circuitry in monkeys and man. The contributions of various components of the KNDy system to normal reproductive development and function will be explored using receptor agonists and antagonists. Exogenous pulsatile kisspeptin and opioid receptor antagonists will be assessed as a potential treatment tools for patients with certain types of hypogonadal disorders.
