Determining the role of circadian synchrony between the mother and fetus in birth outcomes

每年约有1500万名婴儿早产，面临严重的短期和长期健康问题。尽管已有广泛的研究集中于对抗早产，但我们对调节妊娠长度的过程并没有透彻的了解。最近感兴趣的一个领域集中在昼夜节律的中断如何影响生殖结果。一个例子是在怀孕期间轮班工作或上夜班的妇女，因为她们早产以及其他生殖并发症的发生率较高，如先兆子痫和胎儿生长受限。然而，关于昼夜节律在出生时间中的作用以及在这一过程中哪些组织可能是最重要的，人们知之甚少。我们最近发现，母体和胎儿组织的日常节律在怀孕期间都会发生可靠的变化，不同的昼夜节律突变基因类型会改变出生时间。我们的工作，在老鼠身上，试图检验这一基本假设，即在生理学上母婴昼夜节律的协调决定了怀孕的长度和分娩的时间。为了验证这一假设，这项提议将把新的计算方法与双色实时成像相结合，同时在母亲及其胎儿体内进行子宫内基因表达，以确定母体和胎儿的昼夜节律如何以及何时同步(目标1)。此外，我们将利用我们进行胚胎移植和操纵特定细胞类型中的昼夜节律基因的能力来确定胎儿和母体组织对出生时间的相对贡献(目标2)。这些目标的完成将决定母胎昼夜节律沟通在分娩时间中的作用。这些发现可以帮助我们理解怀孕期间的时序紊乱如何导致生殖并发症，并确定预防早产的潜在治疗目标。

Each year, roughly 15 million infants are born premature and at risk for dire short- and long-term health problems. Despite the extensive research that has focused on combating prematurity, we do not have a thorough understanding of the processes that regulate gestation length. One area of recent interest has focused on how disruptions of circadian rhythms affect reproductive outcomes. One example is women who undergo rotating shift work or work the night shift during pregnancy, as they have a higher incidence of preterm birth as well as other reproductive complications, such as preeclampsia and intrauterine growth restriction. However, little is known about the role of circadian rhythms in the timing of birth and which tissues may be most important in this process. We recently found that both maternal and fetal tissues exhibit daily rhythms that reliably change during pregnancy and that different circadian mutant genotypes alter birth timing. Our work, in mice, seeks to test the fundamental hypothesis that maternal-fetal coordination of circadian rhythms in physiology determines gestation length and the time of day of delivery. To test this hypothesis, this proposal will combine novel computational methods with two-color, real-time imaging of in utero gene expression simultaneously in the mother and their fetuses to determine how and when maternal and fetal circadian rhythms synchronize (aim 1). Furthermore, we will utilize our ability to perform embryo transfers and to manipulate circadian genes in specific cell types to determine the relative contributions of the fetus and maternal tissues to the timing of birth (aim 2). Completion of these aims will determine the role of maternal-fetal circadian communication in the timing of birth. These findings could help us understand how chronodisruption during pregnancy can lead to reproductive complications and identify potential therapeutic targets to prevent preterm birth.