Mechanisms Underlying GnRH Metabolite Action

Henry M Jackson Fdn For Advmt Of Military Medicine, Bethesda MD

Investigators

Abstract

Gonadotropin-releasing hormone (GnRH) was first isolated in mammals and shown to be the primary regulator of the reproductive system. After this initial discovery, GnRH has been shown to be part of a larger family of similar peptides found in the brain and other tissues. To date, over 20 family members have been identified in vertebrate and invertebrates, and they have been shown to have diverse functions. As with most peptides, GnRH is regulated at the synthesis level (gene expression and translation) and at secretion. In addition, GnRH is processed by a zinc metalloendopeptidase EC 3.4.24.15 (EP24.15) that cleaves the hormone at the covalent bond between the 5th and 6th residue of the decapeptide (Tyr5-Gly6) to form a subproduct, GnRH-(1-5). This subproduct of GnRH, GnRH-(1-5) is bioactive and has been shown to regulate gene expression and facilitate reproductive behavior in brain and other tissues. Dr. Wu?s laboratory recently identified an orphan G-protein coupled receptor (GPR) that binds to GnRH-(1-5) with high affinity and this receptor is likely to be the mediator of GnRH-(1-5) activities. To that end, this project will use two physiological approaches and an anatomical approach to test this hypothesis. These studies will identify a ligand and a function for an orphan receptor. The collective data will underscore the importance of peptide processing in regulating neurobiological processes that is beyond the attributes of the parent peptide ? an evolutionary influence to increase diversity. The results of this study and the identification of a novel receptor may also resolve many present quandaries in the current utilization of the parent peptide. Broader Impact: The project will include a significant training component in which a postdoctoral fellow, 1-2 graduate students and at least 6 college students and high school students will receive training in neuroendocrine techniques. Each student will be involved in one specific aim supervised by a senior member of the laboratory. The high school student will participate in lab meetings, they will conduct some of the experiments and present at high school?s science fair, ultimately submitting their work to local and national science fairs and competitions.