PLACENTAL PLASTICITY, FETAL GROWTH AND DEVELOPMENTAL PROGRAMMING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 来自流行病学和动物研究的越来越多的证据表明，次优的宫内环境是个体出生后健康的关键决定因素。我们的工作假设是，发育关键阶段的产前侮辱通过改变基因表达模式，对胎盘的生长、结构和功能产生不同的影响，从而改变胎儿的生长、器官发育和成人疾病的风险。该项目的目标是了解调节胎盘生长发育的机制，以及将心血管和代谢性疾病的风险“传递”给后代的因素。使用胎盘功能不全的非人灵长类动物模型，我们将描述副胎盘叶血管在两个不同胎龄结扎后胎盘基因表达谱的变化(使用候选基因方法和微阵列分析)。我们将记录血浆和羊水生物标记物，用于推测导致胎盘代偿性生长的途径。我们将研究几个可能受胎盘生长机制影响的基因家族，包括：i)生长调节因子(例如血管内皮生长因子、胎盘生长因子)，ii)炎症介质和促氧化剂(例如IL-6、肿瘤坏死因子-α和8-异前列腺素)，以及iii)营养转运体(例如葡萄糖转运体)。分子和生化研究将得到一系列超声测量的补充，以将胎儿血流动力学和区域循环(即脑、肺和胎盘血流)的变化与怀孕期间胎儿的身体大小和比例相关联，以了解可能调节胎儿生长的血液动力学影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is increasing evidence from epidemiologic and animal studies that a sub-optimal intrauterine environment is a key determinant of the postnatal health of individuals. Our working hypothesis is that a prenatal insult at critical stages of development produces varied effects on placental growth, structure and function through altered gene expression patterns, which modify fetal growth, organ development and the risk of adult disease. The goal of this project is to understand the mechanisms that regulate placental growth and development as well as the factors that "transmit" risk to the offspring for cardiovascular and metabolic diseases. Using a non-human primate model of placental insufficiency, we will characterize alterations in placental gene expression profiles (using a candidate gene approach as well as microarray analyses), after the vascular supply to the accessory placental lobe has been ligated at two different gestational ages. We will document plasma and amniotic fluid biomarkers for putative pathways responsible for compensatory placental growth. We will investigate several families of genes that are likely affected by placental growth mechanisms, including: i) Growth Regulating Factors (e.g., vascular endothelial growth factor, placental growth factor), ii) Inflammatory Mediators and Pro-oxidants (e.g.,interleukin-6, tumor necrosis factor-alpha and 8-isoprostane), and iii) Nutrient Transporters (e.g., glucose transporters). Molecular and biochemical studies will be complemented by serial ultrasound measurements to correlate fetal hemodynamics and changes in regional circulations (i.e., cerebral, pulmonary and placental blood flow), with fetal body size and proportions through pregnancy in order to understand the hemodynamic influences, which may regulate fetal growth.