Inhibin is an ovarian-produced protein that regulates pituitary FSH release and follicle function. We hypothesize that the ability of specific cells in the reproductive tract to respond to inhibin is controlled by a specific inhibin receptor present on the cell membrane. Therefore, we will identify the inhibin receptor. The inhibin receptor has been partially purified from the gonadal tumors that arise from inhibin-deficient mice (alpha-subunit knockout mice). Using affinity purification techniques, inhibin receptor proteins have been purified. They have been labeled inhibin receptor based on the facts that they were membrane associated and bound inhibin A and not activin A. Moreover, the proteins are not follistatin. Based on this preliminary data, the current grant proposes to continue these studies and to purify and then characterize the inhibin receptor. Several alternative approaches to the identification of the receptor are also proposed. Receptor activation stimulates cytoplasmic signaling molecules. Candidate signal proteins have been identified (Smad2 and Smad4) and we have shown that these proteins are activated by inhibin in granulosa cells. We hypothesize that normal, inhibin-regulated granulosa cell function is dependent on the appropriate interaction of ligand with Smad2 or Smad4 and that alteration in the inhibin signal transduction pathway will lead to abnormal follicle function. These tenets will be tested in granulosa cell culture. The transcriptional response of inhibin-regulated promoters will be measured following over-expression of normal or mutated signal proteins in a granulosa cell line, GRM02. The genetic sequence that is responsive to inhibin signals will be identified. These studies will establish the causal relationship between the inhibin system and normal and abnormal follicle function and lead toward a more complete understanding of key regulating protein in the ovarian-pituitary axis.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037096-04
Application #
6476808
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Taymans, Susan
Project Start
1998-12-15
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
4
Fiscal Year
2002
Total Cost
$223,038
Indirect Cost
Name
Northwestern University at Chicago
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Evanston
State
IL
Country
United States
Zip Code
60201
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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