The Role of Leptin in Placental Development

描述(申请人提供)：胎盘发育是一个复杂的过程，涉及多种细胞类型之间的相互作用，并可能受到怀孕期间母亲营养的影响。此外，成人疾病的胎儿起源假说认为，孕期母亲的营养对胎儿未来的成人健康有影响。支持这一建议的假设是，激素瘦素影响胎盘发育过程中的多个步骤。瘦素是由脂肪细胞产生的，因此是营养对胎盘发育影响的潜在中介。在这项建议的指导阶段，第一个特定的目标是确定瘦素在植入前发育过程中滋养层细胞规格中的作用。这些实验将定位瘦素在早期胚胎中的位置，并确定瘦素的分布是否是滋养层细胞形成所必需的。第二个目的是确定瘦素诱导滋养层细胞侵袭的机制。这些实验将探索细胞信号通路和基因表达的变化，这些信号通路和基因表达变化是瘦素刺激滋养细胞入侵的基础。在这项提案的独立阶段，第一个具体目标是确定瘦素是否在营养对胎儿和胎盘编程的影响中起中介作用。动物将被安排在有或没有瘦素治疗的情况下进行限制饮食，并确定对胎盘发育和成人肥胖的影响。第二个特定目的是确定瘦素对胎盘细胞类型分化的影响。滋养层干细胞将用于研究瘦素在巨细胞、合体滋养层细胞和海绵滋养层细胞分化中的作用。我的目标是建立一个独立的生殖生物学实验室，研究母体环境对胎盘发育的影响。这笔赠款将提供一个机会，在一个领先的胎盘生物学实验室接受特定技术和更广泛的科学问题方面的培训，并允许我在这个实验室从事一项独立的研究。拟议的项目至少在两个方面与人类健康有关。首先，滋养层侵袭不足与先兆子痫有关，先兆子痫是妊娠最常见的并发症，可能是致命的。本项目将研究其中一个对滋养细胞侵袭的影响。其次，这个项目将增加我们对怀孕期间母亲营养可能影响胎盘发育甚至成人健康的方式的理解。；

DESCRIPTION (provided by applicant): Placental development is a complex process that involves interactions among multiple cell types and may be affected by maternal nutrition during pregnancy. Further, the fetal origin of adult disease hypothesis posits that maternal nutrition during pregnancy has consequences for the future adult health of the fetus. The hypothesis underlying this proposal is that the hormone leptin influences multiple steps in the process of placental development. Leptin is produced by fat cells, and thus is a potential mediator of the effects of nutrition on placental development. In the mentored phase of this proposal, the first specific aim is to determine the role of leptin in trophoblast cell specification during preimplantation development. These experiments will localize leptin in the early embryo and determine whether the distribution of leptin is required for trophoblast cells to form. The second aim is to determine the mechanism of leptin-induced trophoblast invasiveness. These experiments will explore the cell signaling pathways and changes in gene expression that underlie leptin stimulation of trophoblast invasion. In the independent phase of this proposal, the first specific aim is to determine whether leptin mediates effects of nutrition on fetal and placental programming. Animals will be placed on a restricted diet with or without leptin treatment, and the effects on placental development and adult adiposity determined. The second specific aim is to determine effects of leptin on placental cell type differentiation. Trophoblast stem cells will be used to study the role of; leptin in the differentiation of giant cell, syncytiotrophoblast cell, and spongiotrophoblast cell types. My goal is to establish an independent laboratory in reproductive biology to pursue research on the effects of maternal environment on placental development. This grant would provide an opportunity for training in specific techniques and broader scientific questions in a leading laboratory in placental biology, and would allow me to pursue an independent line of research in this laboratory. The proposed project is relevant to human health in at least two ways. First, insufficient trophoblast invasion is associated with pre-eclampsia, the most common complication of pregnancy, and one which can be fatal. This project will examine one of the influences on trophoblast invasion. Second, this project will increase our understanding of the ways in which maternal nutrition during pregnancy, may influence placental development, and even adult health. ;