Regulation of angiogenesis at the maternal-fetal interface

母胎界面血管生成的调节

• 批准号: 386700-2010
• 负责人: Tayade, Chandrakant
• 金额: $ 2.77万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=529022
• 关键词: Regulation; angiogenesis; maternal; fetal; interface

Blastocyst implantation, placentation and successful pregnancy require coordinated vascular development/ remodeling and functional adaptations on both maternal-fetal sides of implantation sites. At implantation, a richly vascularized endometrium is critical for successful implantation. Shortly after implantation, growth of this vasculature is essential to facilitate nutrients and oxygen transport to the conceptus. Immune cells, in particular natural killer cells, dendritic cells and macrophages are recruited to the implantation sites where they have pivotal roles in angiogenesis and regulation of maternal-fetal cross talk but their recruitment signals are poorly understood. Alterations in angiogenesis and immune cell functions lead to fetal loss. We hypothesize that immune cells are recruited and positioned within the maternal-fetal interface by specific chemokine signals and their angiogenic properties are regulated by specific microRNAs. Using our previously established technical approach of Laser Capture Microdissection for studies in pig and mice, Aim1 will characterize chemokine recruitment signals from maternal and fetal sides (their suitable receptors/decoy receptors) for immune cells. Aim2 will characterize important angiogenic factors and cytokines regulating pregnancy success in immune cell-subsets. Aim3 will define specific MicroRNAs regulating angiogenesis and immune cell development. Using targeted locked nucleic acid probes in mice, specific microRNAs identified in aim#3 will be blocked and in-vivo effects during pregnancy will be evaluated in Aim4. Proposed study will be conducted at specific time points in pregnancy to capture endometrial enrichment of immune cells and initiation of angiogenesis (gestation day (gd) 15 and 20 in porcine pregnancy and gd8, 10, 12 in mice). These studies will provide novel insights into pathways of immune cell recruitment and their role in angiogenesis regulation and ultimately fetal survival in species with non-invasive epitheliochorial placenta (pig) and invasive hemochorial placenta (mice). Outcomes from this study will help to target immune cells and their products for reducing fetal loss in pigs. Proposed research will provide training for 2 graduate and 3 summer students.

胚泡植入、胎盘形成和成功妊娠需要在植入部位的母胎两侧协调血管发育/重塑和功能适应。在着床时，丰富的血管子宫内膜是成功着床的关键。植入后不久，这种血管的生长对于促进营养和氧气向胚胎的运输是必不可少的。免疫细胞，特别是自然杀伤细胞、树突状细胞和巨噬细胞被招募到植入部位，在那里它们在血管生成和母婴串扰调节中发挥关键作用，但对它们的招募信号知之甚少。血管生成和免疫细胞功能的改变会导致胎儿丧失。我们假设免疫细胞通过特定的趋化因子信号被招募并定位在母胎界面上，它们的血管生成特性受特定的microRNAs调控。使用我们先前建立的用于猪和小鼠研究的激光捕获显微切割技术方法，Aim1将表征来自母体和胎儿侧(其合适的受体/诱饵受体)的免疫细胞趋化因子招募信号。AIM2将在免疫细胞亚群中表征调节妊娠成功的重要血管生成因子和细胞因子。AIM3将定义调控血管生成和免疫细胞发育的特定microRNAs。在小鼠身上使用定向锁定的核酸探针，Aim#3中确定的特定microRNAs将被阻断，Aim4将评估怀孕期间的体内效应。拟议的研究将在怀孕的特定时间点进行，以捕捉子宫内膜免疫细胞的丰富和血管生成的启动(怀孕15天和20天，猪怀孕15天和20天，小鼠8天，10天，12天)。这些研究将为免疫细胞募集的途径及其在血管生成调节中的作用提供新的见解，并最终在具有非侵袭性上皮绒毛胎盘(猪)和侵袭性血绒毛膜胎盘(鼠)的物种中存活。这项研究的结果将有助于针对免疫细胞及其产品减少猪的胎儿损失。拟议的研究将为2名研究生和3名暑期学生提供培训。