The Harvard Reproductive Endocrine Sciences Center has been dedicated to translational research in reproduction for the past 20 years. The Center uses interdisciplinary approaches to define the genetic control of puberty and reproduction in the human incorporating techniques from clinical investigation, human genetics, molecular biology, and bioinformatics. Broadly, the Center aims to continue its discovery program to find novel genes that control reproductive function and elucidate their biology to enhance the diagnostics, treatment, and counseling of patients with infertility and reproductive disorders. PROJECT 1 (Pl: Crowley) will utilize modern genetic and genomic tools to identify genes involved in the biology of GnRH neuronal development capitalizing on our unique cohort of >1,300 patients/families with isolated GnRH deficiency that has been assembled by our Phenotyping, Genotyping, &Bioinformatics Core (Core B). It will then chart the genotype-phenotype spectrum of these new genes and determine their role in both congenital GnRH deficiency and more common reproductive disorders. PROJECT 2 (Pl: Seminara) will utilize human genetics and murine studies to elucidate the interplay of the Neurokinin B and KISS1/KISS1R pathways. These studies will also draw on our unique cohort of GnRH deficient patients as well as targeted gene deletions of these systems in mice. PROJECT 3 (Pl: Kaiser) will explore the molecular biology of G-coupled protein receptors (GPCRs) and the mechanisms by which they impact human reproduction. Using mutations in both ligands and their cognate GPCRs, including those from Project 1, Project 3 will chart their biologic activity and use in vitro techniques to elucidate their cellular actions and the effects of mutations on identified reproductive pathways. CORE A: will provide organizational, logistical, and administrative support for the center investigators;CORE B: will recruit patients for genetic studies/detailed phenotyping and manage the Progeny database;CORE C: will provide web based patient centered information on reproductive disorders and will link other investigators to our Progeny database.

Public Health Relevance

This project aims to identify and study the genes which control puberty and reproduction in the human. Better understanding the genetic control of reproduction will enable us to develop better diagnostic tests, treatments, and counseling for patients with infertility and reproductive disorders.

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 #
5U54HD028138-22
Application #
8240414
Study Section
Special Emphasis Panel (ZHD1-DSR-L (32))
Program Officer
De Paolo, Louis V
Project Start
1997-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
22
Fiscal Year
2012
Total Cost
$2,044,861
Indirect Cost
$720,695
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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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
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
Choi, Jin-Ho; Balasubramanian, Ravikumar; Lee, Phil H et al. (2015) Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency. J Clin Endocrinol Metab 100:E1378-85
Min, Le; Leon, Silvia; Li, Huan et al. (2015) RF9 Acts as a KISS1R Agonist In Vivo and In Vitro. Endocrinology 156:4639-48
Stamou, M I; Cox, K H; Crowley Jr, William F (2015) Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the ""-Omics"" Era. Endocr Rev 36:603-21

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