Regulation of Pregnancy-Dependent Adaptations

描述(申请人提供)：血液绒毛胎盘在许多哺乳动物物种中使用，包括啮齿动物和灵长类动物。它确保了母体和胚胎之间最亲密的接触。这种类型的胎盘植入具有明显的优势，但也对母亲和胎儿的健康构成了相当大的挑战。专门的适应发生在女性生殖道内，以适应发育中的胚胎和胎儿的需要。这些变化包括子宫基质细胞分化为蜕膜以及相关的母体子宫血管的广泛发育。子宫血管的改变是向发育中的胎儿输送营养物质的基础。子宫胎盘血管重塑的控制机制尚不清楚。妊娠早期的自然杀伤(NK)细胞和妊娠后期的滋养细胞是妊娠相关血管变化的关键调节细胞。我们已经确定了一种影响子宫胎盘血管系统发育的体内可重复性方法。怀孕的啮齿动物暴露在低压低氧环境中会导致子宫胎盘血管的深刻重塑。这种对母体子宫血管的影响是巨大的，并在很大程度上保护胎儿免受宫内生长受限的影响。我们假设，低压-低氧挑战会导致正常妊娠依赖性子宫胎盘血管调节的夸大。此外，我们认为这些母胎适应的失败会导致母亲和/或胎儿的病理改变。在这项研究项目中，我们概述了旨在评估母体对低压缺氧的代偿反应的细胞和分子机制，包括NK细胞和滋养细胞衍生细胞因子催乳素样蛋白-A(PLP-A)的调节作用。这项实验利用了缺乏NK细胞、干扰素-Y和PLP-A的基因操作突变小鼠品系。已经提出了新的想法和新的研究方法来阐明控制妊娠建立和维持所必需的基本过程的调节机制。

DESCRIPTION (provided by applicant): Hemochorial placentation is utilized in many mammalian species including rodents and primates. It ensures the most intimate contacts between maternal and embryonic compartments. This type of placentation presents apparent advantages but also considerable challenges to the well being of mother and fetus. Specialized adaptations occur within the female reproductive tract to accommodate the needs of the developing embryo and fetus. Among these changes are the differentiation of uterine stromal cells into decidua and the extensive development of the associated maternal uterine vasculature. The uterine vascular modifications are fundamental to the delivery of nutrients to the developing fetus. Mechanisms underlying the control of uteroplacental vascular remodeling are not well understood. The key regulators of the pregnancy-dependent changes in the vasculature are natural killer (NK) cells during early pregnancy and trophoblast cells during the latter stages of pregnancy. We have identified a reproducible in vivo method impacting the development of the uteroplacental vasculature. Exposure of pregnant rodents to hypobaric-hypoxia results in a profound remodeling of uteroplacental blood vessels. This effect on the maternal uterine vasculature is dramatic and largely protects the fetus from intrauterine growth restriction. We hypothesize that the hypobaric-hypoxia challenge results in an exaggeration of normal pregnancy-dependent uteroplacental vascular adjustments. Furthermore we propose that failures in these maternal-fetal adaptations result in pathologies in the mother and/or fetus. In this research project, we outline experiments designed to evaluate cellular and molecular mechanisms underlying the maternal compensatory response to maternal hypobaric-hypoxia, including the regulatory roles of NK cells and the trophoblast-derived cytokine, prolactin-like protein-A (PLP-A). The experimentation utilizes genetically manipulated mutant mouse strains deficient in NK cells, interferon-y, and PLP-A. Novel ideas and a novel research approach have been presented to elucidate regulatory mechanisms controlling fundamental processes essential for the establishment and maintenance of pregnancy.