Understanding Placental Adaptation to Maternal Malnutrition

 描述（由申请方提供）：在家畜和人类中，最佳胎儿生长取决于胎盘中充足的营养输送。我们的长远目标是 发现和了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，胎儿生长受损与家畜和人类新生儿发病率和死亡率增加有关。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。本提案的目标是利用自然种群差异， 绵羊（作为农业上重要的食用动物以及与人类相关的研究的公认生物医学模型）来阐明胎盘可以适应母体营养不良以支持不同程度的胎儿生长的机制。为了实现这一目标，我们将使用体型和条件相似的单胎妊娠母羊进行一系列营养研究，这些母羊携带由相似雄性和超数排卵供体雌性产生的胚胎。我们以前采用这种策略，并观察到增加的差异，在营养限制母羊的胎儿生长水平。我们将利用这一自然群体的差异，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。具体目标是：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）研究营养限制母羊中胎盘血管生长和功能的调控机制; 3）鉴定所选营养素在营养限制母羊中调节胎盘生长和功能的贡献。这项研究具有创新性，因为它将为研究胎盘的生长，功能和适应性开发一种独特的动物模型。此外，我们将采用新的手术策略，允许回顾性分析早期胎盘基因表达的基础上，在妊娠后期胎儿生长的速度。拟议研究的完成有望填补我们现有知识中的一个关键空白，为胎盘生长和功能提供新的见解，因为它们与观察到的胎儿生长速率谱有关。拟议研究的转化成果包括胎盘功能的生物标志物，以及确定新的营养和遗传靶点，用于开发治疗策略，以增强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.