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

确定母亲和胎儿之间昼夜节律同步性在出生结果中的作用

• 批准号: 10413817
• 负责人: Keenan Bates
• 金额: $ 3.27万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413817
• 关键词: Address; Affect; Area; Behavior; Birth; Brain; Circadian Dysregulation; Circadian Rhythms; Circadian gene expression; Clinic; Color; Communication; Complex; Computing Methodologies; Coupling; Data; Embryo Transfer; Embryonic Development; Exhibits; Feedback; Fetal Development; Fetal Growth Retardation; Fetal Tissues; Fetus; Food; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Goals; Health; Human; Hypothalamic structure; Image; Incidence; Intervention; Investigation; Knowledge; Lead; Length; Mammals; Maps; Measures; Monitor; Mothers; Mus; Mutation; Outcome; Physiological Processes; Physiology; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Premature Birth; Premature Infant; Premature Labor; Process; Research; Risk; Role; Signal Transduction; System; Testing; Time; Tissues; Translating; Translations; United States; Uterus; Woman; Work; Wrist; bioluminescence imaging; cell type; circadian; circadian pacemaker; clinical care; experimental study; fetal; fetus cell; genetic predictors; improved; in utero; interest; mutant; neonate; novel; personalized medicine; premature; prevent; real-time images; reproductive; reproductive outcome; shift work; temporal measurement; therapeutic target; tool

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.

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的风险。尽管针对早产进行了广泛的研究，但我们对调节妊娠长度的过程还没有透彻的了解。最近人们感兴趣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女性，因为她们早产以及其他生殖并发症（如先兆子痫和宫内生长受限）的发生率较高。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个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。我们在小鼠身上的工作旨在检验一个基本假设，即生理学中母胎昼夜节律的协调决定妊娠长度和分娩时间。为了检验这一假设，该提案将新颖的计算方法与母亲及其胎儿子宫内基因表达的双色实时成像相结合，以确定母亲和胎儿的昼夜节律如何以及何时同步（目标 1）。此外，我们将利用我们的能力进行胚胎移植和操纵特定细胞类型中的昼夜节律基因，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交流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。