Mouse Model For Amniotic Fluid Volume Regulation

描述(由申请人提供)：全面了解 羊水量的控制具有重要的临床意义。我们有 先前在胎膜中发现了一条血管通路 羊水从羊膜腔转移到胎儿血液中。这 通路是由血管表面的微血管网络构成的 胎盘，绵羊的羊膜和绒毛膜内也有。我们假设 血管内皮生长因子(VEGF)是血管生成的决定因素 这一膜内通路的吸收能力，因此是一个重要的 羊水量调节器。在本申请中，我们建议 建立羊水过多和羊水过少的小鼠模型。模型将是 靶向抑制或诱导血管内皮细胞生长因子基因表达 胎膜和胎盘。鼠标模型的优点是，它 允许研究血管内皮生长因子在膜内吸收中的作用 操纵。提出了三个具体目标。具体目标1建议 VEGE抑制血管内皮生长因子基因表达导致羊水过多 反义序列与胎儿过表达血管内皮生长因子引起的羊水过少 胎膜和胎盘。胎儿肺发育异常所致 将研究羊水量的变化。《特定目标2》将展开调查 羊膜、绒毛和胎盘微血管的增殖 羊水过多或羊水过少的怀孕小鼠。羊水的变化 液体体积与膜内微血管密度及血管内皮生长因子基因表达的关系 表达将是相关的。《特定目标3》将检查胎儿和产后 羊水过多或羊水过少模型的生长模式，以及 探讨成年后血压紊乱的发展状况。整体而言 假说是在怀孕的小鼠中，羊水量的变化 可以通过对血管内皮生长因子基因的遗传操作来诱导，从而产生模型 适用于羊水过多和羊水过少。拟议的研究是一项创新的研究 了解羊水量调节的方法。的模型。 羊水过多和羊水过少允许对胎儿和出生后进行调查 羊水量异常所致的生长发育缺陷 子宫。这些研究的结果将对诊断和 妊娠期羊水量紊乱的治疗。

DESCRIPTION (provided by applicant): A comprehensive understanding of the control of amniotic fluid volume is of major clinical importance. We have previously identified a vascular pathway within the fetal membranes for the transfer of fluid from the amniotic compartment into the fetal blood. This pathway is constituted by a network of microvessels on the surface of the placenta and, in sheep, within the amnion and chorion as well. We hypothesize that vascular endothelial growth factor (VEGF) is the determining factor for the absorptive capacity of this intramembranous pathway, thus an important regulator of amniotic fluid volume. In the present application, we propose to develop a mouse model of polyhydramnios and oligohydramnios. The model will be generated using targeted suppression or induction of VEGF gene expression in the fetal membranes and placenta. The advantage of the mouse model is that, it allows the study of the role of VEGF in intramembranous absorption by genetic manipulation. Three specific aims are proposed. Specific Aim 1 proposes to produce polyhydramnios by suppression of VEGF gene expression using a VEGE antisense sequence and oligohydramnios by over-expression of VEGF in the fetal membranes and placenta. Abnormalities in fetal lung development due to amniotic fluid volume changes will be studied. Specific Aim 2 will investigate the proliferation of microvessels in the amnion, chorion and placenta of pregnant mice with polyhydramnios or oligohydramnios. The change in amniotic fluid volume in relation to intramembranous microvessel density and VEGF gene expression will be correlated. Specific Aim 3 will examine fetal and postnatal growth patterns in the polyhydramniotic or oligohydramniotic models, and explore the development of blood pressure disorders in adulthood. The overall hypothesis is that in the pregnant mouse, alterations in amniotic fluid volume can be induced by genetic manipulation of the VEGF gene thus generating models for polyhydramnios and oligohydramnios. The proposed study is an innovative approach to understanding amniotic fluid volume regulation. The models of polyhydramnios and oligohydramnios allow investigation of fetal and postnatal growth and developmental defects due to abnormal amniotic fluid volume in utero. Results from these studies will be important for diagnosis and treatment of amniotic fluid volume disorders during pregnancy.