The Role of Leptin in Placental Development

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， 在怀孕期间受到母亲营养的影响。此外，成人疾病的胎儿起源假说 假设怀孕期间的产妇营养会对胎儿未来的成年健康产生影响。在 特别是，已经表明，怀孕早期严重的热量限制会导致风险增加， 肥胖和心血管疾病的风险。的机制 这种情况发生的原因尚不清楚，但时间表明，改变胎盘发育可能是 涉案支持这一建议的假设是，激素瘦素影响多个步骤， 胎盘发育的过程。瘦素是由脂肪细胞产生的，因此是一种潜在的介质， 营养对胎盘发育和随后的成人健康的影响。第一个具体目标是 确定瘦素缺乏是否介导营养对胎儿和胎盘编程的影响。动物 将被置于限制饮食，有或没有瘦素替代，以及对胎盘发育的影响 和成人肥胖症。胎盘的大小、形态、基因表达和基因甲基化将被 考察此外，将对接受治疗的母亲的后代进行整个成年期的随访，以确定长期的 饮食和瘦素替代对肥胖和血脂的影响。第二个具体目标是 在细胞水平上确定瘦素对胎盘分化的影响。滋养层干细胞 用于研究瘦素在巨细胞、合体滋养层细胞、 海绵滋养层细胞类型。除了该提案的科学目标外，这一“通往 独立”项目是建立一个独立的生殖生物学实验室进行研究 母体环境对胎盘发育的影响。

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 origins of adult disease hypothesis posits that maternal nutrition during pregnancy has consequences for the future adult health ofthe fetus. In particular, it has been shown that severe caloric restriction during early pregnancy results in increased risk of obesity and cardiovascular disease when the affected fetus reaches middle age. The mechanisms by which this occurs are poorly understood, but the timing suggests that altered placental development may be involved. 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 ofthe effects of nutrition on placental development and subsequent adult health. The first specific aim is to determine whether leptin shortage mediates effects of nutrition on fetal and placental programming. Animals will be placed on a restricted diet with or without leptin replacement, and effects on placental development and adult adiposity determined. Placental size, morphology, gene expression, and gene methylation will be examined. In addition, the offspring of treated mothers will be followed through adulthood to determine longterm effects of diet and leptin replacement on obesity and lipid profiles. The second specific aim is to determine effects of leptin on placental differentiation at the cellular level. Trophoblast stem cells will be used to study the role of leptin in the differentiation of giant cell, syncytiotrophoblast cell, and spongiotrophoblast cell types. In addition to the scientific aims ofthe proposal, a goal of this "Pathways to Independence" project is to establish an independent laboratory in reproductive biology to pursue research on the effects of maternal environment on placental development.