This application requests continuing support for the Center for Reproductive Research (CRR) at Northwestern University and its goal to contribute to a more comprehensive understanding of female fertility and infertility. The purpose of our center is to explore ovarian follicle dynamics from the perspective of structure-function relationships of the follicle unit and the hormones that regulate it. The intent of the original CRR proposal was to facilitate the transfer of basic biological, biochemical and biophysical findings to clinical care by bringing experts in engineering, biophysics and structural biology together with reproductive endocrinologists and clinical investigators. We explored the relationship between the holo-follicular structure and its ability to sense and respond appropriately to endocrine hormones and paracrine acting factors (inhibin and activin) and made significant new observations about how these mechanisms are regulated biophysically. We solved four major hormone structures at the atomic level and the structure of a transcription factor bound to DNA. We also developed an in vitro follicle maturation system that supports immature follicle growth, oocyte maturation and the birth of live, healthy offspring. By all measures, the first four years of this center have been productive and effective in translating the work from basic reproductive biology to biophysics and biomaterials to the bedside. The projects proposed for the next five years of work are innovative and again focus on major questions in reproductive science using a structure-function approach. Our scientists and clinical investigators work as a highly effective team to ensure the timely, bidirectional transfer of information from clinical problem to the bench and back. To accomplish our goals, four projects are proposed. It is known that fertility and oocyte quality diminish with age and oocytes from older women frequently have abnormal meiotic spindles, including abnormal chromosome alignment and microtubular matrix composition and aneuploidy. Lonnie Shea and team (Project I) developed an in vitro follicle maturation system, an attractive model for exploring age-related oocyte health. They will test the hypothesis that oocyte abnormalities arise from lack of coordinated growth of the holo-follicular complex. Kelly Mayo and Ishwar Radhakrishnan (Project II) will continue their exploration of transcription factor interactions that direct hormone-dependent gene expression in the granulosa cell. Specifically, they will ask how SF-1 and LRH-1 nuclear receptors regulate inhibin-a subunit gene expression at the molecular level in conjunction with the cAMP-dependent factor CREB and the ovarian factors GATA-4 and GATA-6. Project III is led by Ted Jardetzky, who is studying the atomic structure of TGF-B superfamily ligands in complex with regulating binding proteins. He is specifically interested in oocyte-derived GDF-9 and BMP-15, which control follicle development. Finally, Project IV will examine the relationship of structural rigidity to follicular function and is collaboration between Teresa Woodruff and Andrea Dunaif. By combining basic biochemical, biomaterial and biophysical approaches with medicine, we will remain at the forefront of new discoveries in the structure-function relationships of reproductive biology. Moreover, each of our continuing projects reaffirms our commitment to translate our findings to the bedside, and thereby contribute to the overall health of women.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Study Section
Special Emphasis Panel (ZHD1-DSR-L (54))
Program Officer
De Paolo, Louis V
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Northwestern University at Chicago
Obstetrics & Gynecology
Schools of Medicine
United States
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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
Tagler, David; Makanji, Yogeshwar; Anderson, Nicholas R et al. (2013) Supplemented ?MEM/F12-based medium enables the survival and growth of primary ovarian follicles encapsulated in alginate hydrogels. Biotechnol Bioeng 110:3258-68
Mutharasan, Priscilla; Galdones, Eugene; Penalver Bernabe, 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
Skory, Robin M; Bernabe, Beatriz Penalver; 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
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
Hornick, J E; Duncan, F E; Shea, L D et al. (2013) Multiple follicle culture supports primary follicle growth through paracrine-acting signals. Reproduction 145:19-32
Tagler, David; Tu, Tao; Smith, Rachel M et al. (2012) Embryonic fibroblasts enable the culture of primary ovarian follicles within alginate hydrogels. Tissue Eng Part A 18:1229-38
Zhu, Jie; Lin, S Jack; Zou, Chao et al. (2012) Inhibin ýý-subunit N terminus interacts with activin type IB receptor to disrupt activin signaling. J Biol Chem 287:8060-70

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