Understanding Placental Adaptation to Maternal Malnutrition

 描述(申请人提供)：在家养动物和人类中，最佳的胎儿生长取决于通过胎盘提供足够的营养。我们的长期目标是 发现和理解调节胎盘生长和功能的激素、细胞和分子机制，以支持最佳的胎儿生长。重要的是，胎儿发育受损与牲畜和人类新生儿发病率和死亡率的增加有关。此外，与成人发病疾病的发育起源有关的新证据突出了不良子宫环境对终身健康的额外长期后果。这项建议的目标是利用自然人口差异，通过 绵羊既是农业上重要的食用动物，也是与人类有关的研究的公认生物医学模型)，以阐明胎盘可以适应母亲营养不良的机制，以支持不同程度的胎儿生长。为了实现这一目标，我们将进行一系列的营养研究，使用的是身体大小和状况相似的独生子女怀孕母羊，携带的胚胎来自相似的雄性和超数排卵的捐赠者雌性。我们以前采用过这一策略，并观察到营养受限的母羊胎儿生长水平的差异增加。我们将利用这种自然的群体差异，通过比较基于胎儿生长的个体的上、下四分位数来阐明控制胎盘生长和功能的机制。具体目的是：1)阐明胎儿基因型和宿主子宫环境对胎儿发育的相对贡献；2)研究营养受限母羊胎盘血管生长和功能的调控机制；3)确定精选营养素在调节营养受限母羊胎盘生长和功能中的作用。这项研究具有创新性，因为它将开发一种独特的动物模型来研究胎盘的生长、功能和适应。此外，我们将采用新的手术策略，根据妊娠晚期的胎儿生长速度，对早期胎盘基因的表达进行回顾性分析。这项拟议研究的完成有望填补我们现有知识的一个关键空白，因为它提供了关于胎盘生长和功能的新见解，因为它们与观察到的胎儿生长速度的频谱有关。拟议研究的翻译结果包括胎盘功能的生物标记物，以及确定新的营养和遗传目标，以制定治疗策略，促进营养不良母亲的胎儿生长。

 DESCRIPTION (provided by applicant): In domestic animals and humans, optimal fetal growth is predicated on sufficient nutrient delivery across the placenta. Our long-range goal is to discover and understand the hormonal, cellular, and molecular mechanisms regulating placental growth and function to support optimal fetal growth. Importantly, impaired fetal growth is associated with increased incidence of neonatal morbidity and mortality in both livestock species and humans. In addition, emerging evidence related to developmental origins of adult-onset disease highlight the additional long- term consequences of a poor uterine environment on lifelong health. The goal of this proposal is to capitalize on natural population variance using the sheep, (serving as both an agriculturally important food animal as well as an accepted biomedical model for studies related to humans) to elucidate the mechanisms by which the placenta can adapt to maternal malnutrition to support varying degrees of fetal growth. To achieve this goal we will conduct a series of nutritional studies using singleton pregnant ewes of similar body size and condition, carrying embryos generated from similar males and superovulated donor females. We have previously employed this strategy and observed increased variance in levels of fetal growth in nutrient restricted ewes. We will capitalize on thi natural population variance by comparing the upper and lower quartiles of individuals based upon fetal growth to elucidate mechanisms controlling placental growth and function. Specific aims are to: 1) elucidate the relative contributions of fetal genotype and the host uterine environment on fetal development; 2) investigate mechanisms governing placental vascular growth and function in nutrient-restricted ewes; and 3) identify the contribution of select nutriens in regulating placental growth and function in nutrient-restricted ewes. This research is innovative because it will develop a unique animal model for the study of placental growth, function, and adaptation. In addition, we will employ novel surgical strategies allowing for retrospective analysis of early placental gene expression based on rates of fetal growth in late gestation. Completion of the proposed research is expected to fill a critical gap in our existing knowledge by providing novel insights into placental growth and function as they relate to the spectrum of observed rates of fetal growth. Translational outcomes of the proposed research include biomarkers for placental function as well as the identification of novel nutritional and genetic targets for the development of therapeutic strategies to enhance fetal growth in undernourished mothers.