Five years of support are requested to study the aging pituitary ovarian axis. We seek to understand pituitary-ovarian communication via follicle-stimulating hormone (FSH). It is well known that in women over the age of 35 fertility declines compared with younger women. Infertility clinics report decreased responsiveness of older women to exogenous FSH preparations. This project will focus on the response of the aging ovary to a change in relative abundance of two major human (h) FSH glycoforms. The classic hFSH possessing both alpha subunit and beta subunit oligosaccharides is designated tetra-glycosylated hFSH and a novel hFSH glycoform possessing only alpha subunit oligosaccharides is designated di-glycosylated hFSH. Women aged 21-24 express more di-glycosylated hFSH than tetra-glycosylated hFSH, perimenopausal women express slightly less di-glycosylated hFSH, while post-menopausal women express primarily tetra-glycosylated hFSH. Project 1 will investigate the changes in relative abundance of hFSH glycoforms during the menstrual cycle that are associated with increasing age and study mechanisms for glycan modulation of FSH receptor binding and activation. Project 2 will compare the activities of hFSH glycoforms in a variety of signal transduction assays in the ovary in order to identify possible mechanisms that enhance the biological activity of di-glycosylated hFSH. The differential effects of both glycoforms on bone resorption will also be studied. Project 3 will create mouse models to test the hypothesis that both hFSH glycoforms are necessary for reproductive function. A double hFSH? glycosylation mutant will replace the normal mFSH? gene. This line will be crossed with FSH? null mice to see if it can rescue female infertility. Purified hFSH glycoforms will also be tested in vivo using FSH null mice. The WSU FSH process core laboratory (Core B) will provide well characterized purified hFSH glycoforms, to all projects. The initial products will be di-glycosylated hFSH and tetra-glycosylated hFSH, which are of interest to all the scientific projects, but are not available from other sources. Recombinant di-glycosylated hFSH will be expressed first, due to low abundance in natural sources. Core B will characterize glycan populatlons at each occupied N-glycosylation site, thereby providing fully characterized glycoforms with known, rather than assumed glycosylation differences. Core B will also provide cell culture and assay services to project investigators. The WSU bioinformatics core (Core C) will provide a data-sharing platform readily accessible to all investigators via the internet. The outcome of this research will be a better understanding of the mechanisms for reduced ovarian responsiveness with aging that may lead to the development of more effective FSH preparations for treating infertility. While currently available preparations work well in young women, they become increasingly ineffective in older women, requiring higher doses and prolonged administration yet producing fewer oocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG029531-05
Application #
8449608
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (J5))
Program Officer
Fuldner, Rebecca A
Project Start
2009-04-15
Project End
2014-03-31
Budget Start
2013-05-15
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,165,852
Indirect Cost
$229,673
Name
Wichita State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
053078127
City
Wichita
State
KS
Country
United States
Zip Code
67260
Wang, Huizhen; Larson, Melissa; Jablonka-Shariff, Albina et al. (2014) Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice. Proc Natl Acad Sci U S A 111:5735-40
Talbott, Heather; Delaney, Abigail; Zhang, Pan et al. (2014) Effects of IL8 and immune cells on the regulation of luteal progesterone secretion. Reproduction 148:21-31
Fu, David; Lv, Xiangmin; Hua, Guohua et al. (2014) YAP regulates cell proliferation, migration, and steroidogenesis in adult granulosa cell tumors. Endocr Relat Cancer 21:297-310
Ulloa-Aguirre, Alfredo; Reiter, Eric; Bousfield, George et al. (2014) Constitutive activity in gonadotropin receptors. Adv Pharmacol 70:37-80
Kumar, T Rajendra (2014) Extragonadal FSH receptor: is it real? Biol Reprod 91:99
Bousfield, George R; Butnev, Vladimir Y; Butnev, Viktor Y et al. (2014) Hypo-glycosylated human follicle-stimulating hormone (hFSH(21/18)) is much more active in vitro than fully-glycosylated hFSH (hFSH(24)). Mol Cell Endocrinol 382:989-97
Ulloa-Aguirre, Alfredo; Dias, James A; Bousfield, George et al. (2013) Trafficking of the follitropin receptor. Methods Enzymol 521:17-45
Bousfield, George R; Dias, James A (2011) Synthesis and secretion of gonadotropins including structure-function correlates. Rev Endocr Metab Disord 12:289-302
Kumar, T Rajendra (2011) The "Glow"rious Sertoli and germ cells: mouse testis development visualized in multi-colors. Biol Reprod 84:201-4
Wehbi, Vanessa; Tranchant, Thibaud; Durand, Guillaume et al. (2010) Partially deglycosylated equine LH preferentially activates beta-arrestin-dependent signaling at the follicle-stimulating hormone receptor. Mol Endocrinol 24:561-73

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