The leading cause of both infant mortality and long-term health morbidities in children is preterm birth (PTB). PTB has a higher incidence in women who work night shifts, suggesting that disruptions in circadian rhythms (daily sleep/wake and activity cycles that are aligned with environmental stimuli) contribute to PTB. Further supporting this idea are reports that low fecundity, pregnancy loss, and abnormal delivery are found commonly in mice with mutations in genes that control circadian rhythms. Furthermore, there is strong evidence that the timing of birth is determined by maternal signals, but how the circadian system affects maternal signals is not well understood. The ?master clock? within the brain, the suprachiasmatic nucleus (SCN), regulates ?peripheral clocks? in all cells, including those in reproductive tissues. Little is known about the roles of circadian rhythms in maternal reproductive tissues and the timing of birth. The central hypothesis of this proposal is that the maternal circadian clock plays a key role in determining the timing of birth by regulating peripheral clocks within the uterus and secretion of the pregnancy maintenance hormone progesterone (P4). This hypothesis is based on preliminary and published data. Preliminary work revealed that mice with short circadian periods deliver earlier than wild-type mice, both the uterus and the cervix have endogenous rhythms, and pregnant dams become active progressively earlier each day, beginning on day four of pregnancy, and then abruptly revert back to later onset of locomotor activity two to three days before delivery. These shifts align with a rise in P4 production beginning in early pregnancy and a dramatic drop in P4 a few days before delivery. P4 withdrawal in mice mimics a functional P4 withdrawal in humans and triggers labor. Early P4 withdrawal is a common risk factor for PTB in humans. I will address my hypothesis by pursuing the following three aims: 1) define the pattern of uterine and cervical clock gene expression throughout pregnancy, 2) determine the role of the uterine and SCN clocks in the timing of birth and 3) define the relationship between levels of P4 and activity rhythms in late pregnancy. Completion of these aims will yield several basic science outcomes that are significant because they will add to our understanding of the relationship between the circadian and reproductive system as they relate to timing of birth. These findings could be important first steps towards reducing the number of preterm births to nights shift workers and/or ameliorating the harmful effects of PTB. The proposed studies support a postdoctoral training plan that includes interdisciplinary technical training, scientific meetings and consultation with leaders in both reproductive and circadian fields, which will prepare the applicant for beginning the transition to early investigator.
Prematurity is the greatest contributor to infant mortality worldwide and is more common in women with work schedules that are misaligned with their normal sleep/wake cycle (night shifts). The purpose of this study is to test whether the maternal circadian clock plays a key role in determining the timing of birth by regulating clocks within the brain, the uterus and the cervix and to understand the role of progesterone in this process. From these studies we hope to lay the groundwork for developing strategies to treat preterm birth.
