Key words: human reproduction, functional genomics, metagenomics, steroid hormone action, endocrine disruptors, mucosal immunity, ovarian cancer, stem cells, translational science. Our laboratory investigates molecular mechanisms underlying: normal and abnormal human endometrial development and function; normal and abnormal ovarian follicle development and steroidogenesis; and the human female reproductive tract as a portal of entry for infection. We translate basic science findings to clinical applications. Endometrium. Human endometrium is a steroid hormone responsive tissue that receives an embryo or regenerates in non-conception cycles. It is also a mucosal tissue providing immune surveillance and protection against infectious agents ascending to the upper reproductive tract and systemically. Abnormalities of the endometrium can result in abnormal bleeding, poor regenerative capacity, endometriosis, implantation disorders (infertility, miscarriage, pre-eclampsia, intrauterine fetal growth restriction), infection, polyps, hyperplasia, and cancer. Our laboratory has extensively investigated the roles of steroid hormones, IGFs, and Wnt family members in endometrial cellular proliferation and differentiation. We have also pursued gene discovery in normal endometrium across the menstrual cycle, in the disorder of endometriosis, recurrent miscarriage, in women with HIV, and in women using the contraceptive gel, nonoxynyl-9. These studies have resulted in identification of basic biologic processes within the tissue in response to steroid hormones normally and in several disease states and therapies, signaling pathways, and molecular markers of disease and potential therapeutic targets. We also study cross-talk between the placenta and the endometrium, and the role of the IGF system in human trophoblast invasion and function. We have found extensive roles for components of the immune system in implantation, which we are actively pursuing. Studies are underway on endometrial stem cells and their relevance to endometrial regeneration and endometriosis, and the progression of ovarian endometriosis to endometriosis-associated ovarian cancer. We are also investigating hESC differentiation down the trophoblast lineage and interactions between the human trophectoderm with endometrial epithelium in a model of the initial stage of implantation in humans. Ovary. Our studies in the ovary focus on the IGF system, using a mouse model in which PAPP-A has been deleted by homologous recombination. The IGF system is critical for ovarian follicle development, dominant follicle selection, granulosa sterodiogenesis, cellular proliferation, and inhibition of apoptosis. We investigate the compromised reproductive phenotype of the PAPP-A mouse and its relevance to human ovarian dysfunction and the effects of endocrine disruptors on ovarian function. The human female reproductive tract as a portal of entry for infection. We are pursuing a metagenomics approach to defining bacterial flora in human vagina under different steroid hormone conditions and in the setting of preterm delivery. Furthermore, we are investigating the role of the endometrium as a portal of entry for male-to-female HIV-1 transmission. We also participate in an NIH clinical trial group on therapies and prevention of sexually transmitted infections in women.
Kao LC, Tulac S, Lobo S, Imani B, Yang JP, Germeyer A, Osteen K, Taylor RN, Lessey BA, Giudice LC. Global gene profiling in human endometrium during the window of implantation. Endocrinology 2002;143:2119-2138.
Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, Osteen K, Lessey BA, Giudice LC. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology 2003;144:2870-2881.
Tierney EP, Tulac S, Huang ST, Giudice LC. Activation of the protein kinase A pathway in human endometrial stromal cells reveals sequential categorical gene regulation. Physiol Genomics 2003 16; 16:47 -66.
Lathi RB, Hess AP, Tulac S, Nayak NR, Conti M, Giudice LC. Dose-dependent insulin regulation of insulin-like growth factor binding protein-1 in human endometrial stromal cells is mediated by distinct signaling pathways. J Clin Endocrinol Metab 2005;90:1599-1606.
Tulac S, Overgaard MT, Hamilton AE, Jumbe NL, Suchanek E, Giudice LC. Dickkopf-1, an inhibitor of Wnt signaling, is regulated by progesterone in human endometrial stromal cells. J Clin Endocrinol Metab. 2006 Apr;91(4):1453-61. Epub 2006 Jan 31.
Hess AP, Hamilton AE, Talbi S, Dosiou C, Nyegaard M, Nayak N, Genbecev-Krtolica O, Mavrogianis P, Ferrer K, Kruessel J, Fazleabas AT, Fisher SJ, Giudice LC. Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators. Biol Reprod. 2007 Jan;76(1):102-17. Epub 2006 Oct 4.
Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007 Aug;148(8):3814-26. Epub 2007 May 17.
Macklon NS, van der Gaast MH, Hamilton A, Fauser BC, Giudice LC. The impact of ovarian stimulation with recombinant FSH in combination with GnRH antagonist on the endometrial transcriptome in the window of implantation. Reprod Sci. 2008 Apr;15(4):357-65.