EGF Family Signaling in Human Implantation

早期胎盘形成的发育异常与多种妊娠和胎儿发育有关。 紊乱对早期流产绒毛的分析显示， 细胞滋养层细胞的侵袭性表型，以及炎症引起的细胞凋亡水平升高， 氧化损伤对调节细胞滋养层分化和存活的新机制的深入了解开始于 随着我们发现肝素结合表皮生长因子样蛋白表达的严重缺陷， 在患有先兆子痫的妇女的胎盘中检测HB-EGF（Leach等人，2002）。EGF是 与滋养层分化为侵袭性表型相关，并且是 滋养层处于低氧水平。虽然HB-EGF可能是滋养细胞侵袭所必需的， 和生存，目前还不清楚HB-EGF的表达和加工是如何调节的氧化应激发现， 早期妊娠丢失。我们的长期目标是开发干预措施， 胎盘对氧化应激的反应，以防止或纠正早期妊娠丢失。正在努力 目的，本申请的目的是了解氧气如何机械调节HB-EGF， 对人胎盘形成过程中滋养层细胞存活和分化的影响。我们的核心假设是 HB-EGF的可用性维持细胞滋养层在生理性缺氧条件下的存活和分化 当暴露于活性氧物质时会受到损害的条件。因此，HBEGF表达失败 可能是导致细胞滋养层细胞进行性凋亡的原因。的 这项研究的基本原理是，了解复氧损伤与HBEGF之间的关系， 可用性及其促进生存的作用将导致筛查、预防和治疗的创新方法。 和/或治疗。因此，预计将产生重大效益，包括：1） 完整了解正常着床，2）关于胎盘分子基础的新见解！ 病理学，和3）有关细胞机制的知识，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