Developmental abnormalities of early placentation are implicated in a variety of pregnancy and fetal disorders. Analysis of villi from early pregnancy loss reveals poor extravillous differentiation of cytotrophoblasts to an invasive phenotype, and elevated levels of apoptosis caused by inflammation and oxidative injury. Insight into a novel mechanism regulating cytotrophoblast differentiation and survival began with our discovery of a profound deficiency in the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in placentae of women with preeclampsia (Leach et al, 2002 ). HB-EGF is associated with differentiation of trophoblast to an invasive phenotype and is required for survival of trophoblast at low oxygen levels. While it appears that HB-EGF could be essential for trophoblast invasion and survival, it is unclear how HB-EGF expression and processing is regulated by the oxidative stress found in early pregnancy loss. Our long-term goal is to develop interventions that can modulate intercellular responses to oxidative stress in the placenta to prevent or rectify early pregnancy loss. Working toward that goal, the objective of this application is to understand mechanistically how oxygen regulates HB-EGF and the effect on trophoblast survival and differentiation during human placentation. Our central hypothesis is that, HB-EGF availability maintains cytotrophoblast survival and differentiation under physiologic hypoxic conditions which is compromised when exposed to reactive oxygen species. Thus, failure to express HBEGF in response to oxidative stress is likely to be responsible for progressive cytotrophoblast apoptosis. The rationale for the proposed study is that understanding the relationship between reoxygenation injury and HBEGF availability and its pro-survival action will result in innovative approaches for screening, prevention and/or treatment. As a consequence, significant benefits are expected to accrue, including: 1) a more complete understanding of normal implantation, 2) new insights regarding the molecular basis of placenta! pathologies, and 3) knowledge pertaining to cellular mechanisms that moderate oxidative stress and promote invasiveness, which is pertinent to other fields, such as cancer biology and toxicology

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 #
5U54HD040093-07
Application #
7666695
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
7
Fiscal Year
2008
Total Cost
$230,832
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Taylor, Hugh S; Alderman Iii, Myles; D'Hooghe, Thomas M et al. (2017) Effect of simvastatin on baboon endometriosis. Biol Reprod 97:32-38
Evans-Hoeker, Emily; Lessey, Bruce A; Jeong, Jae Wook et al. (2016) Endometrial BCL6 Overexpression in Eutopic Endometrium of Women With Endometriosis. Reprod Sci 23:1234-41
Dyson, Matthew T; Kakinuma, Toshiyuki; Pavone, Mary Ellen et al. (2015) Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells. Fertil Steril 104:953-963.e2
Fazleabas, Asgerally T; Braundmeier, Andrea; Parkin, Kirstin (2015) Endometriosis-induced changes in regulatory T cells - insights towards developing permanent contraception. Contraception 92:116-9
Ruiz, Lynnette A; Báez-Vega, Perla M; Ruiz, Abigail et al. (2015) Dysregulation of Lysyl Oxidase Expression in Lesions and Endometrium of Women With Endometriosis. Reprod Sci 22:1496-508
Armant, D R; Fritz, R; Kilburn, B A et al. (2015) Reduced expression of the epidermal growth factor signaling system in preeclampsia. Placenta 36:270-8
Baumann, Claudia; Olson, Mark; Wang, Kai et al. (2015) Arginine methyltransferases mediate an epigenetic ovarian response to endometriosis. Reproduction 150:297-310
Giuliani, Emma; Parkin, Kirstin L; Lessey, Bruce A et al. (2014) Characterization of uterine NK cells in women with infertility or recurrent pregnancy loss and associated endometriosis. Am J Reprod Immunol 72:262-9
Oh, Seo Jin; Shin, Jung-Ho; Kim, Tae Hoon et al. (2013) ?-Catenin activation contributes to the pathogenesis of adenomyosis through epithelial-mesenchymal transition. J Pathol 231:210-22
Bi, Jiajia; Li, Yanfen; Sun, Fengyun et al. (2013) Basigin null mutant male mice are sterile and exhibit impaired interactions between germ cells and Sertoli cells. Dev Biol 380:145-56

Showing the most recent 10 out of 96 publications