The objective of this research proposal is to understand the biosynthetic pathways leading to inhibin secretion from ovarian granulosa cells. The most recognized action of inhibin is to suppress FSH production and secretion by the pituitary gonadotrope in vitro and in vivo. Inhibin levels are regulated during the reproductive cycle to ensure normal FSH-dependent follicle recruitment. Little is known regarding the cellular pathways leading to inhibin biosynthesis, yet, it is the thesis of this grant renewal that these pathways are responsible for the accurate production of this key ovarian feedback hormone and are vital to normal reproductive function. Inhibin A and inhibin B are produced by the granulosa cell of the ovary, however, the secretion patterns for these ligands are distinct, suggesting an underlying control over biosynthesis and release that has not been previously investigated. In addition, the precise mechanism by which many granulosa cell products are targeted toward the antral fluid or the vascular theca cell compartment is not well understood. Our preliminary studies have identified differential secretion patterns of inhibin A and inhibin B during the rat reproductive cycle, described differential compartmentalization of inhibin subunit protein in granulosa cells of developing follicles, and revealed that the biosynthetic processing of inhibin isoforms is regulated. These preliminary studies and the results of the past five years of work suggest that the cellular machinery that regulates inhibin biosynthesis and processing is important to inhibin action and must be investigated in order to more completely understand the function of this ligand in women and men. We hypothesize that inhibin bioactivity relies on post-translational modification including N-linked glycosylation, protein specific routing signals contained in pro-hormone domains, and bioprocessing enzymes that convert bioinactive pro-ligand into mature, bioactive inhibin. There are three interrelated experimental aims in this proposal that will address the central hypothesis and its tenets. These studies are expected to provide insight into the control of inhibin synthesis and release and contribute to a more complete understanding of normal fertility and the mechanisms that underlie fertilityrelated diseases in women resulting from inappropriate hormone action.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037096-09
Application #
7247878
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Taymans, Susan
Project Start
1998-12-15
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
9
Fiscal Year
2007
Total Cost
$283,058
Indirect Cost
Name
Northwestern University at Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Makanji, Yogeshwar; Zhu, Jie; Mishra, Rama et al. (2014) Inhibin at 90: from discovery to clinical application, a historical review. Endocr Rev 35:747-94
Zhu, Jie; Lin, S Jack; Zou, Chao et al. (2012) Inhibin ?-subunit N terminus interacts with activin type IB receptor to disrupt activin signaling. J Biol Chem 287:8060-70
Lin, S Jack; Hu, Yaoxiong; Zhu, Jie et al. (2011) Structure of betaglycan zona pellucida (ZP)-C domain provides insights into ZP-mediated protein polymerization and TGF-beta binding. Proc Natl Acad Sci U S A 108:5232-6
Kim, So-Youn; Zhu, Jie; Woodruff, Teresa K (2011) A truncated, activin-induced Smad3 isoform acts as a transcriptional repressor of FSH* expression in mouse pituitary. Mol Cell Endocrinol 342:64-72
Antenos, Monica; Lei, Lei; Xu, Min et al. (2011) Role of PCSK5 expression in mouse ovarian follicle development: identification of the inhibin ?- and ?-subunits as candidate substrates. PLoS One 6:e17348
Zhu, Jie; Braun, Edward L; Kohno, Satomi et al. (2010) Phylogenomic analyses reveal the evolutionary origin of the inhibin alpha-subunit, a unique TGFbeta superfamily antagonist. PLoS One 5:e9457
Hulvat, Melissa C; Jeruss, Jacqueline S (2009) Maintaining fertility in young women with breast cancer. Curr Treat Options Oncol 10:308-17
Antenos, Monica; Zhu, Jie; Jetly, Niti M et al. (2008) An activin/furin regulatory loop modulates the processing and secretion of inhibin alpha- and betaB-subunit dimers in pituitary gonadotrope cells. J Biol Chem 283:33059-68
Antenos, Monica; Stemler, Michelle; Boime, Irving et al. (2007) N-linked oligosaccharides direct the differential assembly and secretion of inhibin alpha- and betaA-subunit dimers. Mol Endocrinol 21:1670-84
Bristol-Gould, Sarah; Woodruff, Teresa K (2006) Folliculogenesis in the domestic cat (Felis catus). Theriogenology 66:5-13

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