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

每年大约有1500万婴儿早产，面临严重的短期和长期健康问题。尽管广泛的研究集中在对抗早产，但我们对调节妊娠期长度的过程没有彻底的了解。最近关注的一个领域集中在昼夜节律的破坏如何影响生殖结果。一个例子是在怀孕期间轮班工作或上夜班的妇女，因为她们有较高的早产率以及其他生殖并发症，如先兆子痫和子宫内生长受限。然而，人们对昼夜节律在出生时间中的作用以及哪些组织在这一过程中可能最重要知之甚少。我们最近发现，母体和胎儿组织都表现出在怀孕期间可靠变化的每日节律，并且不同的昼夜节律突变基因型会改变出生时间。我们的工作，在小鼠中，试图测试的基本假设，即在生理上的昼夜节律的母胎协调决定妊娠期的长度和一天的交付时间。为了验证这一假设，该提案将结合联合收割机新的计算方法与双色，实时成像子宫内的基因表达，同时在母亲和他们的胎儿，以确定如何以及何时母亲和胎儿的昼夜节律同步（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，以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通信在出生时间中的作用。这些发现可以帮助我们了解怀孕期间的时间中断如何导致生殖并发症，并确定潜在的治疗靶点以预防早产。

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.