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.

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 #
5U54HD028138-20
Application #
7864108
Study Section
Special Emphasis Panel (ZHD1-DRG-D (03))
Program Officer
De Paolo, Louis V
Project Start
1997-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
20
Fiscal Year
2010
Total Cost
$1,516,475
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Crowley, William F; Balasubramanian, Ravi (2017) MicroRNA-7a2 suppression causes hypogonadotropism and uncovers signaling pathways in gonadotropes. J Clin Invest 127:796-797
Maguire, Caroline A; Song, Yong Bhum; Wu, Min et al. (2017) Tac1 Signaling Is Required for Sexual Maturation and Responsiveness of GnRH Neurons to Kisspeptin in the Male Mouse. Endocrinology 158:2319-2329
Abreu, Ana Paula; Kaiser, Ursula B (2016) Pubertal development and regulation. Lancet Diabetes Endocrinol 4:254-264
Simavli, Serap; Abreu, Ana Paula; Kwaan, Mary R et al. (2016) Candidate gene analysis in a case of congenital absence of the endometrium. Fertil Res Pract 2:3
Stamou, M I; Cox, K H; Crowley Jr, William F (2016) Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the ""-Omics"" Era. Endocr Rev 2016:4-22
Cox, Kimberly H (2016) A Bisphenol by Any Other Name... Endocrinology 157:449-51
Min, Le; Nie, Min; Zhang, Anna et al. (2016) Computational Analysis of Missense Variants of G Protein-Coupled Receptors Involved in the Neuroendocrine Regulation of Reproduction. Neuroendocrinology 103:230-9
Goldberg, Mark A; Kaiser, Ursula B (2015) Editorial: The Rise of the Asterisk: One Step to Facilitate Team Science. Mol Endocrinol 29:943-5
Zhu, Jia; Choa, Ruth E-Y; Guo, Michael H et al. (2015) A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 100:E646-54
Simavli, Serap; Thompson, Iain R; Maguire, Caroline A et al. (2015) Substance p regulates puberty onset and fertility in the female mouse. Endocrinology 156:2313-22

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