Molecular regulation of CRH gene expression in the human placenta

大约70%的婴儿死亡是早产造成的。早产发生率为6-10%，在过去30年里，这一比率没有下降。这在很大程度上是因为我们仍然不知道如何控制正常分娩和早产。了解人类怀孕的生理是发现和预防早产的关键一步。我们的小组已经证明了胎盘中激素（促肾上腺皮质激素释放激素，CRH）的产生与母亲携带婴儿的时间长短之间的联系。在早产的妇女中，CRH分泌的增加发生得更早、更快，而在分娩晚的妇女中，CRH分泌的增加发生得更慢。这项工作导致了生物钟的概念，它决定了胎儿在出生前由母亲携带的时间长度，并且胎盘中CRH的产生起着核心作用。我们一直在研究胎盘细胞中CRH基因是如何被控制的。我们已经在CRH基因的DNA中发现了一些区域，这些区域在控制胎盘产生多少CRH方面起着重要作用。本项目中描述的实验将确定控制人类胎盘中CRH产生的分子机制。这将通过检查控制CRH基因的DNA序列，并通过识别实际执行调节功能的蛋白质来完成，这些功能导致胎盘产生的CRH数量增加或减少。这一重要信息将帮助我们更好地了解如何控制正常和早产，并从这些知识中发现和预防早产的新方法。

Approximately 70% of infant death is a result of premature birth. Preterm delivery occurs in 6-10% of pregnancies, and there has been no reduction in this rate in the last 30 years. This is largely because we remain ignorant of how normal and preterm birth is controlled. Understanding the physiology of human pregnancy is a critical step in the development of ways to detect and prevent preterm birth. Our group has demonstrated a link between production of a hormone (corticotropin releasing hormone, CRH) in the placenta and the length of time the baby is carried in the mother. In women who will deliver prematurely the rise in CRH production occurs earlier and more rapidly, while in women who deliver late the rise occurs more slowly. This work has led to the concept of a biological clock that determines the length of time the fetus will be carried by the mother before birth, and in which production of CRH in the placenta plays a central role. We have been studying how the CRH gene is controlled in placental cells. We have discovered some regions in the DNA of the CRH gene which have important roles in controlling how much CRH is made by the placenta. The experiments described in this project will determine the molecular mechanisms that control the production of CRH in the human placenta. This will be done by examining the DNA sequences involved in controlling the CRH gene and by identifying the proteins that actually perform the regulating functions that result in either increased or decreased amounts of CRH being produced by the placenta. This important information will help us better understand how normal and preterm birth is controlled, and from that knowledge new ways to detect and prevent premature birth can be developed.