MOLECULAR REGULATION AND ROLE OF PLACENTA GROWTH FACTOR

胎盘的成功发育需要滋养层细胞和内皮细胞相互作用的协调。事实上，先兆子痫和宫内生长迟缓（IUGR），母亲和胎儿发病率/死亡率的主要原因，与滋养层和内皮细胞功能障碍。然而，负责这些功能缺陷的分子机制知之甚少。我们最近的研究结果表明，滋养层产生有效的血管生成生长因子，胎盘生长因子（P1 GF），并且P1 GF表达在先兆子痫中严重减少。此外，功能性P1 GF受体（flt-1）的滋养细胞促进增殖和抑制细胞凋亡，在早期妊娠和足月滋养细胞，分别。这些数据支持我们的假设，即异常的滋养层P1 GF的产生有助于血管和滋养层缺陷通常与先兆子痫和IUGR。然而，调节滋养层P1 GF表达和自分泌细胞反应的分子机制尚不清楚。因此，以下具体目标将用于定义滋养层中P1 GF的分子调节和功能：1）表征负责整个妊娠期间滋养层P1 GF表达的时间差异的机制，2）通过选择存在于母体-胎儿界面的细胞因子确定滋养层P1 GF产生的正和负调节，3）确定导致先兆子痫滋养层中异常P1 GF表达的机制缺陷，4）描述调节正常滋养层中P1 GF自分泌功能的关键信号转导应答，5）阐明内源性P1 GF在正常滋养细胞中的功能作用。这些研究的结果将提供重要的信息，滋养层衍生的P1 GF的旁分泌能力，以调节血管功能，并会产生新的数据P1 GF作为一种自分泌因子，影响滋养层功能。总的来说，这些目标提供了全面的见解P1 GF在母胎界面的表达，调节和功能，并将有助于更好地了解血管和滋养层功能障碍的先兆子痫和IUGR的特点。

Successful development of the placenta requires coordinated trophoblast and endothelial cell interactions. Indeed, preeclampsia and intrauterine growth retardation (IUGR), the leading causes of maternal and fetal morbidity/mortality, are associated with trophoblast and endothelial cell dysfunction. However, the molecular mechanisms responsible for these functional defects are poorly understood. Our recent findings show that trophoblast produce the potent angiogenic growth factor, placenta growth factor (P1GF), and that P1GF expression is severely reduced in preeclampsia. Furthermore, functional P1GF receptors (flt-1) on trophoblast promote proliferation and inhibit apoptosis in first trimester and term trophoblast, respectively. These data support our hypothesis that aberrant trophoblast production of P1GF contributes to the vascular and trophoblast defects commonly associated with preeclampsia and IUGR. However, the molecular mechanisms regulating trophoblast P1GF expression and autocrine cellular responses are not known. Accordingly, the following specific aims will be used to define the molecular regulation and function of P1GF in trophoblast: l) characterize mechanisms responsible for temporal differences in trophoblast P1GF expression throughout gestation, 2) determine positive and negative regulation of trophoblast P1GF production by select cytokines present at the maternal-fetal interface, 3) determine the mechanistic defects responsible for aberrant P1GF expression in preeclamptic trophoblast, 4) delineate the key signal transduction responses which regulate P1GF autocrine functions in normal trophoblast and, 5) elucidate the functional role of endogenous P1GF in normal trophoblast. Results from these studies will provide critical information regarding the paracrine ability of trophoblast-derived P1GF to regulate vascular function and will produce novel data concerning P1GF as an autocrine factor which influences trophoblast function. Collectively, these aims provide comprehensive insights into the expression, regulation and function of P1GF at the maternal-fetal interface and will facilitate a better understanding of the vascular and trophoblast dysfunctions that are characteristic of preeclampsia and IUGR.