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
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