During the past 15 years, The Harvard Reproductive Endocrine Sciences Center has been dedicated to translational research in reproduction in the human. Its multidisciplinary investigative team and Human Genotyping and Phenotyping Core has now focused on the genetics of the neuroendocrine control of reproduction using unique human populations available to it. During the past cycle, this team identified three new genes that clearly control the migration and/or functioning of GnRH neurons in the human and cause hypogonadotropic hypogonadism in both men and women when mutated. These results indicate that all three are clearly key gatekeepers of reproductive competency in the human. Hence, Project I (KI = W. Crowley) now proposes to characterize the full phenotype/genotype spectrum of FGFR1 mutations in Idiopathic Hypogonadotropic Hypogonadisms (IHH) and Kallmann Syndrome (KS); contrast them with mutations in KAL1; continue to search for new genes in this evolving "GnRH neuronal migratory pathway"; and examine their in vitro biology. Project II (KI = S. Seminara) will now expand the phenotype of mutations in the GPR54 and KISS-1 genes causing IHH; examine the physiology of metastin, the gene product of KiSS-1, in the human; and examine the biologic effects of metastin administration on GnRH secretion in humans; and contrast the phenotype of the kisspeptin1 knock-out in the mouse with that of our GPR54 knockout. Finally, Project III (KI = U. Kaiser) will examine the molecular mechanisms of GPR54's cellular action in the hypothalamus (using GT1-7 cells); define its regulation by sex steroids; and examine the biologic activity of mutations identified in Project lI, in vitro. Together, this ensemble of synergistic approaches should provide swifter transfer of these truths into the human, one of the central goals of our Center.