The actions of inhibin and activin as modulators of pituitary FSH synthesis and secretion and as local regulatory factors within the gonads makes them of key significance for maintaining reproductive fitness and suggests their involvement in reproductive dysfunction (114). Neutralization of inhibin increases follicular maturation and ovulation in animals (115, 116). Ablation of the a inhibin gene in mice results in formation of gonadal stromal cell tumors, implicating inhibin as a tumor-suppressor gene (117). Conversely, over-expression of inhibin in mice results in suppressed fertility and disrupted folliculogenesis (118). In the human, inhibin is an early marker for some types of ovarian cancer (6), is inappropriately regulated in polycystic ovarian syndrome (7) and may be mutated in some cases of premature ovarian failure (8, 9). Transcription factors regulating inhibin expression are also involved in human disease (119, 120), with perhaps the best example being SF-1 mutations in gonadal and adrenal insufficiency and XY sex-reversal (121, 122). This proposal is aimed at understanding how the inhibin gene is expressed and regulated by the pituitary gonadotropins in the ovary and in follicular granulosa cells, focusing on the structural features and interactions of the transcription factors and coactivators important for this regulation. Figure 2 outlines our current understanding of inhibin gene expression during the reproductive cycle, and points to key aspects of this regulation that we plan to further investigate. While the proposed experiments will focus on the inhibin a subunit gene, we expect these findings to be broadly applicable to understanding gonadotropinand cAMP-dependent signaling pathways regulating gene expression in the mammalian ovary. This basic knowledge is expected to provide a foundation for better understanding aberrations of reproductive hormone synthesis and action that in turn lead to dysfunctions or diseases of importance to human health with implications for the treatment of infertility or regulation of fertility (see also Project IV).

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 #
5U54HD041857-10
Application #
8377541
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
10
Fiscal Year
2012
Total Cost
$287,043
Indirect Cost
$90,873
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Hornick, Jessica E; Duncan, Francesca E; Sun, Mingxuan et al. (2015) Age-associated alterations in the micromechanical properties of chromosomes in the mammalian egg. J Assist Reprod Genet 32:765-9
Skory, Robin M; Xu, Yuanming; Shea, Lonnie D et al. (2015) Engineering the ovarian cycle using in vitro follicle culture. Hum Reprod 30:1386-95
Wood, Charles D; Vijayvergia, Mayank; Miller, Frank H et al. (2015) Multi-modal magnetic resonance elastography for noninvasive assessment of ovarian tissue rigidity in vivo. Acta Biomater 13:295-300
Jiao, Ze-Xu; Xu, Min; Woodruff, Teresa K (2014) Age-related increase in aneuploidy and alteration of gene expression in mouse first polar bodies. J Assist Reprod Genet 31:731-7
Shea, Lonnie D; Woodruff, Teresa K; Shikanov, Ariella (2014) Bioengineering the ovarian follicle microenvironment. Annu Rev Biomed Eng 16:29-52
Tagler, David; Makanji, Yogeshwar; Tu, Tao et al. (2014) Promoting extracellular matrix remodeling via ascorbic acid enhances the survival of primary ovarian follicles encapsulated in alginate hydrogels. Biotechnol Bioeng 111:1417-29
Skory, Robin M; Bernabé, Beatriz Peñalver; Galdones, Eugene et al. (2013) Microarray analysis identifies COMP as the most differentially regulated transcript throughout in vitro follicle growth. Mol Reprod Dev 80:132-44
Mutharasan, Priscilla; Galdones, Eugene; Peñalver Bernabé, Beatriz et al. (2013) Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry. J Clin Endocrinol Metab 98:E185-90
Jiao, Ze-Xu; Woodruff, Teresa K (2013) Detection and quantification of maternal-effect gene transcripts in mouse second polar bodies: potential markers of embryo developmental competence. Fertil Steril 99:2055-61
Jiao, Ze-Xu; Woodruff, Teresa K (2013) Follicle microenvironment-associated alterations in gene expression in the mouse oocyte and its polar body. Fertil Steril 99:1453-1459.e1

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