EGF Family Signaling in Human Implantation

早期胎盘发育异常与多种妊娠和胎儿有关 精神错乱。分析早期妊娠丢失的绒毛显示绒毛外分化不良 细胞滋养层细胞向侵袭性表型转化，以及炎症和炎症引起的细胞凋亡水平升高 氧化损伤。对调控细胞滋养层细胞分化和存活的新机制的洞察开始 随着我们发现肝素结合性表皮生长因子样蛋白表达的严重缺陷 子痫前期患者胎盘中的生长因子(HB-EGF)(Leach等人，2002年)。HB-EGF是 与滋养层细胞分化为侵袭性表型有关，是滋养细胞存活所必需的 低氧条件下的滋养细胞。而HB-EGF对滋养层细胞的侵袭可能是必不可少的。 目前尚不清楚HB-EGF的表达和加工如何受到氧化应激的调节 在早孕丢失中。我们的长期目标是开发能够调节细胞间的干预措施 胎盘对氧化应激的反应，以防止或纠正早孕丢失。努力实现这一目标 本应用的目的是从机制上了解氧气如何调节HB-EGF和HB-EGF 胎盘植入对滋养层细胞存活和分化的影响。我们的中心假设是 HB-EGF可维持细胞滋养层细胞在生理性低氧下的存活和分化 当暴露在活性氧物种中时会受到损害的条件。因此，未能表达HBEGF 氧化应激反应可能与细胞滋养层细胞的渐进性凋亡有关。这个 这项研究的基本原理是，了解复氧损伤和HBEGF之间的关系 可获得性及其有利于生存的行动将导致创新的筛查、预防 和/或治疗。因此，预计将产生显著的好处，包括：1)更多 对正常植入的全面了解，2)对胎盘分子基础的新见解！ 病理学，以及3)与缓和氧化应激和 促进侵袭性，这与其他领域有关，如癌症生物学和毒理学

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