The Center For Research in Reproduction and Infertility
The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) supports a national network of Centers through a program called the Specialized Cooperative Centers Program in Reproduction and Infertility Research (SCCPIR). These Centers are created to carry out outstanding scientific research aimed at expanding our knowledge of the processes underlying the success or failure of human reproduction with the ultimate goal of improving human reproductive health. Currently, the SCCPIR network of Centers is located at 14 sites across the country. The Center at University of Illinois at Urbana-Champaign is the newest addition to the SCCPIR program.
Failure of the fertilized embryo to implant into the uterine wall is a major cause of early pregnancy loss and infertility. The Center supports a multidisciplinary team of basic and clinical scientists with a common interest to understand the mechanisms and cellular pathways that control maternal-fetal interactions during early pregnancy and to identify factors that underlie infertility in women suffering from endometriosis, a common gynecologic disorder. Endometriosis is reported to affect approximately 15% of reproductive age women and is observed in 30-40% of women with infertility. The scientists at this Center will employ innovative investigative strategies to identify endometrial factors whose aberrant expression or function leads to endometriosis and infertility. The knowledge gained from these studies will have direct relevance to women’s health. It should aid in developing new molecular diagnostic tools for screening endometrial dysfunction and enable targeted therapeutic strategies for the treatment of infertility.
The University of Illinois at Urbana-Champaign has a long-standing and rich tradition of research and training in reproductive biology that spans the College of Liberal Arts and Sciences, the College of Medicine, and the College of Veterinary Medicine. A program for training both postdoctoral fellows and predoctoral students for research in reproductive biology has been active in this campus for more than forty years. It currently consists of an outstanding group of faculty members with appointments in five complementary campus departments in the three colleges above: Department of Molecular and Integrative Physiology, Department of Cell and Developmental Biology, Department of Veterinary Biosciences, Department of Animal Sciences, and Department of Biochemistry. These faculty members are diverse in their specialties and research interests, but their strong mutual interest in male and female reproductive biology has fostered collaborative research and developed an active environment of training postdoctoral and predoctoral scientists for careers in reproductive biology. The program helps inform trainees through a weekly reproductive biology research conference, an advanced endocrinology course, and sponsorship of research seminars by outstanding reproductive scientists from other institutions. All of the key participants at the SCCPIR Center at UIUC (M. Bagchi, I. Bagchi, B. Katzenellenbogen and P. Cooke) and their lab members are active participants in the reproductive biology training program.
The program leaders at the SCCPIR Center (M. Bagchi, I. Bagchi, B. Katzenellenbogen and P. Cooke) also participate in a NIEHS Environmental Toxicology Training Program, which focuses on endocrine, developmental and reproductive toxicology. The extramural PI (Robert Taylor) is a research mentor in a multidisciplinary Emory University T32 program “Training in Reproductive, Perinatal & Pediatric Epidemiology” funded by NICHD.
The overall objective of the Center of Research in Reproduction and Infertility is to characterize, at molecular and cellular levels, the hormonal pathways that regulate embryo implantation and fertility. Failure of the fertilized embryo to implant into the endometrium is a major cause of infertility. Following its initial attachment to the uterine epithelium, the embryo invades the endometrial stroma, which then undergoes extensive differentiation and remodeling, known as decidualization. Implantation and decidualization are complex processes driven by a cascade of signaling events regulated by the steroid hormones estrogen and progesterone. The central hypothesis of this research program is that defects in these hormonal signaling pathways lead to improper uterine receptivity, decidualization and early pregnancy loss.
Microarray-based gene expression profiling and receptor-coregulator analyses have revealed novel steroid-regulated pathways, providing important insights into the cellular mechanisms by which implantation is controlled. Combination of this new knowledge with functional analysis in gene knockout mouse models will provide a blueprint of the molecular networks that mediate the hormonal regulation of this process. Extension of these analyses to endometrial tissues obtained from normal women as well as those with endometriosis, a common gynecologic disorder associated with reduced fertility, will provide the important translational component of this research.
The research program in the Center is comprised of four complementary, synergistic projects:
Role of C/EBP beta in Uterine Decidualization and Implantation (P.I. Milan K. Bagchi),
Nuclear Receptor Coregulators in Implantation and Uterine Function (P.I. Benita S. Katzenellenbogen),
Regulation of Stromal Differentiation and Implantation by the BMP2 Pathway (P.I. Indrani C. Bagchi), and
Endometriosis as a Clinical Model of Predecidual Dysfunction (P. I. Robert N. Taylor).
Investigators will be aided by an Administrative Core (Leader: Milan K. Bagchi) that will oversee inter-project interactions and data sharing, and a Microscopy Core (Leader: Paul S. Cooke) that will provide gene and protein expression analyses in cells and tissues.
In summary, the research performed at this Center should improve understanding of the mechanisms and cellular pathways that control implantation and help identify factors that underlie infertility in women with endometriosis. They should also aid in developing new molecular diagnostic tools for screening endometrial dysfunction and enable targeted therapeutic strategies for the treatment of infertility.
A close-knit group of basic and clinical scientists from the University of Illinois at Urbana Champaign, Emory University School of Medicine, and Baylor College ofMedicine will participate in this Center.
The Project Leaders
Dr. Milan Bagchi, Center Director and Professor of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign
Dr. Benita Katzenellenbogen, Swanlund Professor of Molecular and Integrative Physiology and Cell and Developmental Biology, University of Illinois at Urbana Champaign
Dr. Indrani Bagchi, Professor of Veterinary Biosciences, University of Illinois at Urbana Champaign
Dr. Robert Taylor, McCord-Cross Professor and Vice Chair for Research, Department of Gynecology and Obstetrics of Emory University School of Medicine
Dr. Milan Bagchi Dr. Benita
Dr. Indrani Bagchi Dr. Robert Taylor
Microscopy Core of the Center
Dr. Paul Cooke, Core Director and Billie Field Professor in the Department of Veterinary Biosciences and, University of Illinois at Urbana Champaign
Dr. Rex Hess, Professor in the Department of Veterinary Biosciences and, University of Illinois at Urbana Champaign
Dr. Francesco DeMayo, Gordon Cain Professor, Department of Molecular and Cellular Biology and Director, Genetically Engineered Mouse Core at the Baylor College of Medicine.
Dr. John Lydon, Associate Professor, Department of Molecular and Cellular Biology at the Baylor College of Medicine.
Dr. Athi Kannan
Dr. Yuechao Zhao
Dr. Quanxi Li
Visiting Assistant Prof.
The goal of this Center is to extend the information obtained from basic cell biological studies and unique animal models to the clinical realm to inform the molecular basis of human infertility associated with endometrial dysfunction. This program, therefore, will serve as a focal point for further development of translational research in reproductive biology and women's health on the U. of I. campus and will be an excellent fit with the university's current mission of enhancing translational research in biology. The establishment of the Center will further stimulate the collaborative research and training in reproductive biology that exists on campu.
The research in this Center is supported by the Eunice Kennedy Shriver NICHD/NIH through a cooperative agreement as part of the Specialized Centers Program in Reproduction and Infertility Research. The Center also receives generous institutional support from the Office of the Vice Chancellor of Research, the School of Molecular and Cellular Biology, and the College of Veterinary Medicine of the University of Illinois Urbana-Champaign.
List of relevant publications by the Principal Investigators of the U54 Center during 2002-2009:
Relevant Publications by Milan K. Bagchi (PI, Subproject I) and by Indrani C. Bagchi (PI, Subproject III)
1. Cheon YP, Li Q, Demayo FJ, Bagchi IC, Bagchi MK 2002 A genomic approach to identify novel progesterone receptor-regulated pathways in the uterus during implantation. Mol. Endocrinol. 16, 2853-2871.
2. Li Q, Wang, J, Armant R, Bagchi MK, Bagchi IC 2002 Calcitonin downregulates E-cadherin expression in rodent uterine epithelium during implantation. J. Biol. Chem. 277, 46447-46455.
3. Bagchi IC, Cheon YP, Li Q, Bagchi MK 2003 Progesterone receptor-regulated gene networks in implantation. Frontiers in Bioscience 8, 852-861.
4. Cheon YP, Xu X, Bagchi MK, Bagchi IC. 2003 Immune-responsive gene 1 (Irg1) is a novel target of progesterone receptor and plays a critical role during implantation in the mouse. Endocrinology 144, 5623-5630
5. Kumar S, Brudney A, Cheon YP, Fazleabas AT, Bagchi IC 2003 Progesterone induces calcitonin expression in the baboon endometrium within the window of uterine receptivity. Biol. Reprod. 68: 1318-1323.
6. Bagchi MK 2004 Mechanism of action of steroid receptor superfamily. In: "The Encyclopedia of Hormones," ed: Helen L. Henry and Anthony W. Norman. Academic Press, NY, vol. 3, 403-410.
7. Cheon YP, Demayo FJ, Bagchi MK, Bagchi IC 2004 Induction of cytotoxic T-lymphocyte antigen-2 beta, a cysteine protease inhibitor in decidua: a potential regulator of embryo implantation. J. Biol. Chem. 279, 10357-10365.
8. Li Q, Cheon YP, Kannan A., Shanker S., Bagchi IC, Bagchi MK 2004 A novel pathway involving progesterone receptor, 12/15-lipoxygenease-derived eicosanoids, and peroxisome proliferator-activated receptor g regulates implantation in mice. J. Biol. Chem. 279, 11570-11581.
9. Liu X, Bagchi MK 2004 Recruitment of distinct chromatin modifying complexes by tamoxifen-complexed estrogen receptor to natural target gene promoters in vivo. J. Biol. Chem. 279, 15050-15058.
10. Chen D, Xu X, Cheon YP, Bagchi MK, Bagchi IC 2004 Estrogen induces expression of secretory leukocyte protease inhibitor in rat uterus. Biol Reprod. 71, 508-514.
11. Bagchi IC, Li Q, Cheon YP, Mantena SR, Kannan A, Bagchi MK 2005 Use of the progesterone receptor antagonist RU 486 to identify novel progesterone receptor-regulated pathways in implantation. Semin Reprod Med. 23:38-45.
12. Li Q, Bagchi MK, Bagchi IC 2006 Identification of a Signaling Pathway involving Progesterone Receptor, Calcitonin and Tissue Tranglutaminase (tTGase) in Ishikawa Endometrial Cells. Endocrinology 147, 2147-2154.
13. Palanisamy GS, Cheon YP, Kim J, Kannan A, Li Q, Sato M, Mantena SR, Sitruk-Ware RL, Bagchi MK, and Bagchi IC 2006 A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice. Mol. Endocrinol. 20: 2784-2795, 2006.
14. Mantena SR, Kannan A, Cheon YP, Li Q, Johnson PF, Bagchi IC, Bagchi MK 2006 C/EBPbeta is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma. Proc Natl Acad Sci U S A. 103:1870-5.
15. Bagchi MK, Mantena SR, Kannan A, Bagchi IC 2006 Control of uterine cell proliferation and differentiation by C/EBPb: functional implications for establishment of early pregnancy. Cell Cycle 5:922-925.
16. Mardon HJ, Bagchi MK, Bagchi IC, Peng C, Karpovich N, Wang Y. 2007 Hormonal and paracrine regulation of embryonic implantation: a workshop report. Placenta 28, Suppl A:S82-4.
17. Jeyakumar M, Liu XF, Erdjument-Bromage H, Tempst P, Bagchi MK. 2007 Phosphorylation of thyroid hormone receptor-associated nuclear receptor corepressor holocomplex by the DNA-dependent protein kinase enhances its histone deacetylase activity. J Biol Chem. 282:9312-22.
18. Li Q, Kannan A, Wang W, Demayo FJ, Taylor RN, Bagchi MK, Bagchi IC. 2007 Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human. J Biol Chem. 282:31725-32.
19. Kim J, Sato M, Li Q, Lydon JP, Demayo FJ, Bagchi IC, Bagchi MK 2008 Peroxisome proliferator-activated receptor gamma is a target of progesterone regulation in the preovulatory follicles and controls ovulation in mice. Mol Cell Biol. 28:1770-82.
20. Laws MJ, Taylor RN, Sidell N, DeMayo FJ, Lydon JP, Gutstein DE, Bagchi MK, Bagchi IC. 2008 Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival. Development.135:2659-68.
21. Plante BJ, Kannan A, Bagchi MK, Yuan L, Young SL. 2009 Cyclic regulation of transcription factor C/EBP beta in human endometrium. Reprod Biol Endocrinol. 7:15.
23. Simon L, Spiewak KA, Ekman GC, Kim J, Lydon JP, Bagchi MK, Bagchi IC, DeMayo FJ, Cooke PS. 2009 Stromal progesterone receptors mediate induction of Indian Hedgehog (IHH) in uterine epithelium and its downstream targets in uterine stroma. Endocrinology. 150:3871-6.
24. Das A, Mantena SR, Kannan A, Evans DB, Bagchi MK, Bagchi IC. 2009 De novo synthesis of estrogen in pregnant uterus is critical for stromal decidualization and angiogenesis. Proc Natl Acad Sci U S A. 106:12542-7.
Relevant Publications by Benita S. Katzenellenbogen (PI, Subproject II)
Harris, H., Katzenellenbogen, J. A., and Katzenellenbogen, B. S. Characterization of the biological roles of the estrogen receptors, ERα and ERβ, in estrogen target tissues in vivo through the use of an ERα-selective ligand. Endocrinology, 143:4172-4177, 2002.
Rajendran, R. R., Nye, A. C., Frasor, J., Balsara, R., Martini, P. and Katzenellenbogen, B. S. Regulation of nuclear receptor transcriptional activity by a novel DEAD box RNA helicase (DP97). J. Biol. Chem., 278:4628-4638, 2003.
Frasor, J., Danes, J. M., Komm, B., Chang, K., Lyttle, C. R., and Katzenellenbogen, B. S. Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: Insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology, 144:4562-4574, 2003.
Frasor, J., Stossi, F., Danes, J. M., Komm, B., Lyttle, C. R. and Katzenellenbogen, B. S. Selective estrogen receptor modulators (SERMs): Discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells. Cancer Research, 64:1522-1533, 2004.
Stossi, F., Barnett, D. H., Frasor, J., Komm, B., Lyttle, C. R. and Katzenellenbogen, B. S. Transcriptional profiling of estrogen-regulated gene expression via estrogen receptor α or estrogen receptor β in human osteosarcoma cells: Distinct and common target genes for these receptors. Endocrinology, 145:3473-3486, 2004.
Park, S.E., Xu, J., Frolova, A., Liao, L., O’Malley, B.W. and Katzenellenbogen, B.S. Genetic deletion of the repressor of estrogen receptor activity (REA) enhances response to estrogen in target tissues in vivo. Molec. Cell. Biol., 25: 1989-1999, 2005.
Frasor, J., Danes, J. M., Funk, C. C. and Katzenellenbogen B. S. Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes. Proc. Natl. Acad. Sci. USA, 102:13153-13157, 2005.
Stossi, F., Likhite, V. S., Katzenellenbogen, J. A. and Katzenellenbogen, B. S. Estrogen-occupied estrogen receptor represses cyclin G2 gene expression and recruits a repressor complex at the cyclin G2 promoter. J. Biol. Chem., 281:16272-16278, 2006.
Chang, E. C., Frasor, J., Komm, B. and Katzenellenbogen, B. S. Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells. Endocrinology,147, 4831-4842, 2006, doi:10.1210/en.2006-0563.
Mussi P, Liao L, Park SE, Ciana P, Maggi A, Katzenellenbogen BS, Xu J, O'Malley BW. 2006 Haploinsufficiency of the corepressor of estrogen receptor activity (REA) enhances estrogen receptor function in the mammary gland. Proc Natl Acad Sci U S A. 103:16716-16721.
Gowri PM, Sengupta S, Bertera S, Katzenellenbogen BS. 2007 Lipin1 Regulation by Estrogen in Uterus and Liver: Implications for Diabetes and Fertility. Endocrinology (in press, Epub)
Stender JD, Frasor J, Komm B, Chang KC, Kraus WL, Katzenellenbogen BS 2007 Estrogen Regulated Gene Networks in Human Breast Cancer Cells: Involvement of E2F1 in the Regulation of Cell Proliferation. Mol Endocrinol. 21: 2112-23.
Chang EC, Charn TH, Park SH, Helferich WG, Komm B, Katzenellenbogen JA, Katzenellenbogen BS 2008 Estrogen Receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding. Mol Endocrinol. 22:1032-43.
Madak-Erdogan Z, Kieser KJ, Kim SH, Komm B, Katzenellenbogen JA, Katzenellenbogen BS. 2008 Nuclear and extranuclear pathway inputs in the regulation of global gene expression by estrogen receptors. Mol Endocrinol. 22:2116-27.
Stossi F, Madak-Erdogan Z, Katzenellenbogen BS 2009 Estrogen receptor alpha represses transcription of early target genes via p300 and CtBP1. Mol Cell Biol. 29:1749-59.
Relevant Publications by Robert N. Taylor (PI, Subproject IV)
1. Zhao D, Pritts EA, Chao VA, Savouret J-F and Taylor RN. Dioxin stimulates RANTES production in an in vitro model of endometriosis. Mol Hum Reprod 8:849-854, 2002
2. Mueller MD, Vigne JL, Pritts EA, Chao V, Dreher E and Taylor RN. Progestins activate vascular endothelial growth factor gene transcription in endometrial adenocarcinoma cells. Fertil Steril 79:386-92, 2003
3. Mueller MD, Pritts EA, Zaloudek CJ, Dreher E and Taylor RN. Regulation of vascular endothelial growth factor by tamoxifen in vitro and in vivo. Gynecol Obstet Invest 55:119-24, 2003
4. Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, Osteen K, Lessey BA and Giudice LC. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology 144:2870-81, 2003
5. Pritts EA, Zhao D, Sohn SH, Chao VA, Waite LL, Taylor RN. Peroxisome proliferator-activated receptor-g ligand inhibition of RANTES production by human endometriotic stromal cells is mediated through an upstream promoter element. Fertil Steril 80:415-20, 2003
6. Tulac S, Nayak NR, Kao LC, Van Waes M, Huang J, Lobo S, Germeyer A, Lessey BA, Taylor RN, Suchanek E and Giudice LC. Identification, characterization, and regulation of the canonical Wnt signaling pathway in human endometrium. J Clin Endocrinol Metab 88:3860-6, 2003.
7. Easwaran V, Lee SH, Inge L, Guo L, Goldbeck C, Garrett E, Wiesmann M, Garcia PD, Fuller JH, Chan V, Randazzo F, Gundel R, Warren RS, Escobedo J, Aukerman SL, Taylor RN and Fantl WJ. b-Catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res 63:3145-53, 2003
8. Lebovic DI, Chao VA and Taylor RN. Peritoneal macrophages induce RANTES (regulated on activation, normal T cell expressed and secreted) chemokine gene transcription in endometrial stromal cells. J Clin.Endocrinol Metab 89:1397-401, 2004
9. Mueller MD, Vigne J-L, Streich M, Tee MK, Raio L, Dreher E, Bersinger NA and Taylor RN. 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases glycodelin gene and protein expression in human endometrium. J Clin Endocrinol Metab 90:4809-4815, 2005
10. Pritts EA, Ryan IP, Mueller MD, Lebovic DI, Shifren JL, Zaloudek CJ, Korn AP, Darney PD and Taylor RN. Angiogenic effects of Norplant® contraception on endometrial histology and bleeding. J Clin Endocrinol. Metab 90:2142-2147, 2005
11. Wieser F, Vigne J-L, Ryan IP, Hornung D, Djalali S and Taylor RN. Sulindac suppresses NF(nuclear factor)kB activation, RANTES gene and protein expression in endometrial stromal cells from women with endometriosis. J Clin Endocrinol Metab, 90:6441-6447, 2005
12. Tee MK, Vigne J-L and Taylor RN. All-trans retinoic acid inhibits VEGF expression in a cell model of neutrophil activation. Endocrinology 147:1264-1270, 2006
13. Peeters LLH, Vigne J-L, Tee MK, Zhao D, Waite LL and Taylor RN. PPAR-γ activation represses VEGF expression in human endometrial cells: Implications for uterine angiogenesis. Angiogenesis 8:373-379, 2006
14. Xu H, Schultze-Mosgau A, Agic A, Diedrich K, Taylor RN, Hornung D. 2006 Regulated upon activation, normal T cell expressed and secreted (RANTES) and monocyte chemotactic protein 1 in follicular fluid accumulate differentially in patients with and without endometriosis undergoing in vitro fertilization. Fertil Steril. 86:1616-20.
15. Wieser F, Cohen M, Gaeddert A, Yu J, Burks-Wicks C, Berga SL, Taylor RN. 2007 Evolution of medical treatment for endometriosis: back to the roots? Hum Reprod Update.13:487-99.
16. Tee MK, Vigne JL, Yu J, Taylor RN 2008 Natural and recombinant human glycodelin activate a proapoptotic gene cascade in monocyte cells. J Leukoc Biol. 83:843-52.
17. Roberts CP, Taylor RN 2008 Applications of estradiol and testosterone assays in the management of the infertile female patient. Steroids.73(13):1328-32.
18. Taylor RN, Yu J, Torres PB, Schickedanz AC, Park JK, Mueller MD, Sidell N. 2009 Mechanistic and therapeutic implications of angiogenesis in endometriosis. Reprod Sci.16:140-6.
19. Weiss G, Goldsmith LT, Taylor RN, Bellet D, Taylor HS. 2009 Inflammation in reproductive disorders. Reprod Sci. 16:216-29.
20. Wieser F, Yu J, Park J, Gaeddert A, Cohen M, Vigne JL, Taylor RN. 2009 A botanical extract from channel flow inhibits cell proliferation, induces apoptosis, and suppresses CCL5 in human endometriotic stromal cells. Biol Reprod. 81:371-7.