PROJECT III (Kl: KAISER) G protein-coupled receptors (GPCRs) are the largest family of transmembrane proteins in vertebrates and are the molecular targets for nearly half of the therapeutic drugs that are prescribed worldwide. The approximately 1,000 members of the GPCR family exhibit a conserved 7-transmembrane domain topology and mediate physiological responses to diverse ligands, such as hormones, neurotransmitters and sensory stimuli. The role of three ligand/receptor pairs, (1) KISS1/KISS1R;(2) PROK2/PROKR2;and (3) TAC3/TACR3, have been implicated in the neuroendocrine regulation of reproduction and have been identified as underlying reproductive disorders. However, there remains much to be learned about the domains of these receptors important to cell surface expression, ligand binding, and activation of cellular signaling pathways relevant to the function of these receptors in the control of GnRH release. The human mutations will serve as tools to learn about the biology of these GPCRs and their ligands, with implications for structure-function relationships of GPCRs. In our first aim we will build on our previous studies of mutations in KISS1 and KISS1R to further define the cellular mechanisms by which KISS1/KISS1R regulate GnRH. In the second aim, our studies will identify proteins (chaperones) that modulate intracellular trafficking of GPCRs involved in the neuroendocrine regulation of reproduction. These studies will focus initially on PROKR2 as a model, and our findings will be extended to studies of KISS1R and TACR3 to determine their general applicability. Finally, we propose to leverage human mutations to elucidate new features of GPCR structure-function relationships, focusing on poorly understood GPCR domains, recently identified and insufficiently studied receptors, and interactions between receptors.

Public Health Relevance

This project aims to gain a better understanding of the mechanisms by which gene mutations affect receptor function. This will enable a better understanding of reproductive disorders and may help develop new diagnostic tools and treatments.

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 #
8375057
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
22
Fiscal Year
2012
Total Cost
$496,270
Indirect Cost
$120,116
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
Abreu, Ana Paula; Macedo, Delanie B; Brito, Vinicius N et al. (2015) A new pathway in the control of the initiation of puberty: the MKRN3 gene. J Mol Endocrinol 54:R131-9
Babwah, Andy V; Navarro, VĂ­ctor M; Ahow, Maryse et al. (2015) GnRH Neuron-Specific Ablation of G?q/11 Results in Only Partial Inactivation of the Neuroendocrine-Reproductive Axis in Both Male and Female Mice: In Vivo Evidence for Kiss1r-Coupled G?q/11-Independent GnRH Secretion. J Neurosci 35:12903-16
Cox, Kimberly H (2015) A Kiss and a PRomise. Endocrinology 156:3063-5

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