Molecular Regulation and Role of Placenta Growth Factor

描述（由申请人提供）：许多产科并发症，包括先兆子痫和宫内生长迟缓（IUGR），这是母体和胎儿发病/死亡的两个更重要的原因，与滋养层功能障碍和异常胎盘血管发育有关。然而，负责这些功能缺陷的分子机制知之甚少。滋养层通常产生有效的血管生成生长因子，胎盘生长因子（PlGF），并表达PlGF受体（flt-1），其以自分泌方式起作用以促进增殖并抑制凋亡。滋养层PlGF表达在体外通过缺氧而独特地降低，并且临床研究表明在先兆子痫中表达显著降低。这些发现支持了我们的假设，即异常滋养层产生的PIGF有助于血管和滋养层缺陷通常与先兆子痫。尽管这种临床重要性，调节滋养层中PIGF表达的分子机制尚不清楚。因此，下面的具体目标将被用来定义的分子机制，调节PIGF基因表达在正常和先兆子痫滋养层。目的1将表征负责滋养层中组成型高PIGF表达的调控启动子区域，并将定义负责滋养层中细胞类型特异性表达的区域。目的2探讨低氧和一氧化氮介导的滋养细胞PIGF表达下调的转录和转录后调控机制。目的3研究mRNA稳定蛋白HuR和AUF-1在正常和先兆子痫滋养细胞中对PIGF表达的调节作用。这些研究的结果将提供关于滋养层组成性表达高水平PIGF的能力的关键信息，并将产生关于缺氧和一氧化氮介导的分子机制的新数据，缺氧和一氧化氮降低先兆子痫期间PIGF的表达。总的来说，这些目标提供了第一个全面的见解滋养层PIGF表达的分子机制调节，这可能会提供新的治疗方法，以扭转与灌注受损妊娠相关的抗血管生成和滋养层凋亡状态。

DESCRIPTION (provided by applicant): Many obstetrical complications, including preeclampsia and intrauterine growth retardation (IUGR), two of the more significant causes of maternal and fetal morbidity/mortality, are associated with trophoblast dysfunction and aberrant placental vascular development. However, the molecular mechanisms responsible for these functional defects are poorly understood. Trophoblast normally produces the potent angiogenic growth factor, placenta growth factor (PIGF) and expresses PIGF receptors (flt-1) which function in an autocrine manner to promote proliferation and inhibit apoptosis. Trophoblast PIGF expression is uniquely reduced by hypoxia in vitro and clinical studies show that expression is significantly reduced in preeclampsia. These findings support our hypothesis that aberrant trophoblast production of PIGF contributes to the vascular and trophoblast defects commonly associated with preeclampsia. Despite this clinical importance, the molecular mechanisms regulating PIGF expression in trophoblast are not known. Accordingly, the following specific aims will be used to define the molecular mechanisms that regulate PIGF gene expression in normal and preeclamptic trophoblast. Aim 1 will characterize regulatory promoter regions responsible for constitutively high PIGF expression in trophoblast and will define regions responsible for the cell type specific expression in trophoblast. Aim 2 will determine transcriptional and post transcriptional regulatory mechanisms mediated by low oxygen tension and nitric oxide that function to decrease trophoblast PIGF expression. Aim 3 will investigate functional roles that the mRNA stabilizing proteins, HuR and AUF-1, have in regulating PIGF expression in normal and preeclamptic trophoblast. Results from these studies will provide critical information regarding the ability of trophoblast to constitutively express high levels of PIGF and will produce novel data concerning the molecular mechanisms mediated by hypoxia and nitric oxide which decrease PIGF expression during preeclampsia. Collectively, these aims provide the first comprehensive insights into the molecular mechanisms regulating trophoblast PIGF expression which may provide new therapeutic approaches to reverse the anti-angiogenic and trophoblast apoptotic states associated with perfusion compromised pregnancies.