Dissecting the participation of cold shock proteins in reproductive processes: relevance of trophoblast specific YB-1 expression for embryo development

剖析冷休克蛋白在生殖过程中的参与：滋养层特异性 YB-1 表达与胚胎发育的相关性

• 批准号: 404991393
• 负责人: Professorin Dr. Ana Claudia Zenclussen
• 金额: --
• 依托单位: Department Umweltimmunologie und Core Facility Studien
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/404991393?language=en
• 关键词: Dissecting; participation; cold; shock; proteins

The detailed study of pregnancy-associated processes is of pivotal importance for the development of strategies to help reproductively challenged couples. Uterine adaptations to pregnancy are crucial for placentation, in particular for the remodeling of the spiral arteries, a process that implies the conversion of existent spiral arteries into thin-walled arteries with as an adaptation to the increasing blood volume. Suboptimal remodeling cause an inadequate supply of nutrients and/or exchange of gases and waste between the mother and fetus that can lead to pregnancy complications such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE). Not only do these changes danger pregnancy itself but also they greatly influence adult health later. Although research has significantly advanced in the last years, still much work is necessary to understand the cellular and molecular mechanisms underlying IUGR and/or PE. An accurate understanding of the basic mechanisms governing both, implantation and placentation is urgently needed. This application aims to understand the participation of cold shock proteins that, until now, have not been studied in the context of pregnancy. Our first experiments suggest a correlation of YB-1 transcript numbers with IUGR. In placental tissue from patients with IUGR fetuses, YB-1 mRNA was significantly decreased compared to controls. Thus, low YB-1 levels may be related with poor trophoblast physiology.YB-1 +/- females presented an increased number of IUGR feto-placental units compared to the controls at days 8, 10 and day 12 of pregnancy as analyzed by ultrasound. At day 12, placentas from heterozygote mating combinations presented histological abnormalities, such as disorganized area of spongiotrophoblasts and thin labyrinth. No homozygote fetuses were viable after day 12. We found that animals born to YB-1+/- mothers had thicker artery walls with narrower lumens, resulting in enhanced wall-to-lumen ratio. The fact that YB-1+/+ implantations from YB-1+/- mothers also had increased ratios suggests that the uterine environment may play a role in the development of SA. Reduced lumen in these animals means an insufficient blood supply to the fetus and thus, a reduced availability of nutrients and oxygen that can lead to growth restriction while in uterus. Hence, we hypothesize that YB-1 mediates relevant pregnancy-associated processes, including placentation and spiral artery remodeling. Trophoblast-specific YB-1 may have the capacity to regulate the finely orchestrated balance between invasion, proliferation, differentiation, apoptosis, and angiogenesis that is essential for the well-being of the fetus and its proper development. By combining elegant animal models and analysis of human tissue samples, we expect to unravel the participation of cold shock proteins in reproduction.

详细研究妊娠相关过程对于制定帮助生殖困难夫妇的战略至关重要。子宫对妊娠的适应对于胎盘形成至关重要，特别是对于螺旋动脉的重塑，这一过程意味着现有的螺旋动脉转化为薄壁动脉，以适应不断增加的血容量。次优重塑导致母亲和胎儿之间的营养供应不足和/或气体和废物交换，这可能导致妊娠并发症，如宫内生长受限（IUGR）和先兆子痫（PE）。这些变化不仅会危及怀孕本身，而且会极大地影响成年后的健康。虽然研究在过去几年中取得了显着进展，但仍有许多工作需要了解IUGR和/或PE的细胞和分子机制。目前迫切需要对着床和胎盘形成的基本机制有一个准确的认识。该应用程序旨在了解冷休克蛋白的参与，到目前为止，尚未在怀孕的背景下进行研究。我们的第一个实验表明YB-1转录本数量与IUGR相关。在IUGR胎儿患者的胎盘组织中，与对照组相比，YB-1 mRNA显著降低。因此，低YB-1水平可能与滋养层生理功能较差有关。超声分析显示，与对照组相比，YB-1 +/-雌性在妊娠第8、10和12天出现IUGR胎儿胎盘单位数量增加。在第12天，从杂合子交配组合的胎盘出现组织学异常，如海绵滋养细胞和薄迷路区紊乱。第12天后无纯合子胎仔存活。我们发现YB-1+/-母亲所生的动物具有较厚的动脉壁和较窄的管腔，导致壁腔比增强。来自YB-1+/-母亲的YB-1+/+流产也有增加的比率，这一事实表明子宫环境可能在SA的发展中起作用。这些动物的管腔减少意味着胎儿的血液供应不足，因此，营养物质和氧气的可用性降低，可能导致在子宫内生长受限。因此，我们假设YB-1介导相关的妊娠相关过程，包括胎盘形成和螺旋动脉重塑。滋养层细胞特异性YB-1可能具有调节侵袭、增殖、分化、凋亡和血管生成之间的精细协调平衡的能力，这对于胎儿的健康及其正常发育至关重要。通过结合优雅的动物模型和对人体组织样本的分析，我们希望解开冷休克蛋白在生殖中的参与。