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的协调相互作用。事实上，先兆子痫和宫内发育迟缓(IUGR)是母婴发病率/死亡率的主要原因，与滋养细胞和内皮细胞功能障碍有关。然而，导致这些功能缺陷的分子机制却知之甚少。我们最近的研究结果表明，滋养细胞产生强大的血管生成生长因子-胎盘生长因子(P1GF)，并且P1GF在子痫前期表达严重减少。此外，滋养层细胞上的功能性P1GF受体(Flt-1)可促进早孕滋养层细胞的增殖，抑制滋养层细胞的凋亡。这些数据支持我们的假设，即滋养层细胞异常产生P1GF是导致血管和滋养层缺陷的原因，通常与子痫前期和IUGR有关。然而，调控滋养层细胞P1GF表达和自分泌细胞反应的分子机制尚不清楚。因此，我们将利用以下特定目标来确定滋养层细胞中P1GF的分子调控和功能：(1)确定滋养层细胞P1GF表达在整个妊娠过程中的时间差异的机制；2)通过选择存在于母胎界面的细胞因子来确定滋养层细胞P1GF产生的正向和负向调节；3)确定导致子痫前期滋养层细胞P1GF异常表达的机制缺陷；4)阐明在正常滋养层细胞中调节P1GF自分泌功能的关键信号转导反应；5)阐明内源性P1GF在正常滋养层细胞中的功能作用。这些研究结果将提供关于滋养层细胞来源的P1GF调节血管功能的旁分泌能力的关键信息，并将产生关于P1GF作为一种影响滋养层功能的自分泌因子的新数据。总而言之，这些目标提供了对P1GF在母胎界面的表达、调节和功能的全面见解，并将有助于更好地了解以先兆子痫和IUGR为特征的血管和滋养细胞功能障碍。

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.