Preterm labor is a huge clinical, social and economic burden. Defining the basic mechanism underlying preterm labor will help alleviate this devastating global concern. Animal models that spontaneously develop preterm delivery without luteolysis are powerful tools for studying the underlying mechanism as they more closely mimic human parturition. A new mouse model of preterm delivery using uterine-specific deletion of the Trp53 gene encoding p53 has been developed, and these mice have normal ovulation, fertilization, and implantation. However, post-implantation uterine decidual cells show terminal differentiation and senescence- associated growth restriction with increased levels of p21 and pAKT, two factors known to participate in the senescence process. Furthermore, pAKT has been known to activate the mTOR pathway, which is heavily implicated in metabolism and ageing. Surprisingly, uterine deletion of p53 and premature uterine ageing increases the incidence of preterm birth. These findings underscore the central hypothesis that premature uterine senescence plays a central role in premature labor. Since increased maternal age is a risk factor for preterm labor in women and since p53 function declines in ageing mice, premature uterine senescence mediated by mTOR and p21 signaling pathways may promote premature delivery. This hypothesis will be tested and accomplish the objectives of this application with the following specific aims: (1) Determine the effects of inhibition of mTORC1 signaling on uterine senescence and the incidence of preterm birth in mice conditionally deleted of uterine p53.
This aim will test the working hypothesis that mTOR (mammalian target of rapamycin) signaling plays a critical role in uterine senescence and preterm delivery. (2) Determine the effects the superimposition of p21 deletion on conditional deletion of p53 has on uterine senescence and preterm birth.
This aim will test the working hypothesis that increased p21 levels lead to premature uterine senescence and preterm delivery. Identification of a distinct, targetable pathway controlling preterm labor will have a significant impact on our understanding of the etiology of prematurity and may lead to the development of prevention and treatment strategies specifically targeting the mTOR pathway and premature uterine senescence. Thus, this research provides the groundwork for strategies to decrease the incidence of preterm labor and reduce the clinical, financial, and emotional burden worldwide. Further, as this is a conditional deletion of p53 in the uterus, deletion of p53 in other organs may prove to be an excellent model of ageing and may promote further understanding of the interaction between ageing, senescence, and mTOR signaling.

Public Health Relevance

of this research to public health Preterm labor is a significant clinical, social, and economic burden. Prematurity is a direct cause of nearly 30% of all neonatal deaths, totaling more than one million each year. In addition, many babies who survive premature birth suffer serious long-term disabilities. Using transgenic mouse models, the proposed research will test the hypothesis that premature uterine senescence resulting from heightened mammalian target of rapamycin (mTOR) signaling is a major cause of preterm delivery and that inhibiting this signaling will reverse this debilitating event.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Murthy, Mahadev
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Lanekoff, Ingela; Cha, Jeeyeon; Kyle, Jennifer E et al. (2016) Trp53 deficient mice predisposed to preterm birth display region-specific lipid alterations at the embryo implantation site. Sci Rep 6:33023
Sones, Jenny L; Cha, Jeeyeon; Woods, Ashley K et al. (2016) Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model. JCI Insight 1:
Yuan, Jia; Cha, Jeeyeon; Deng, Wenbo et al. (2016) Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proc Natl Acad Sci U S A 113:E8079-E8088
Deng, Wenbo; Cha, Jeeyeon; Yuan, Jia et al. (2016) p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing. J Clin Invest 126:2941-54
Cha, Jeeyeon; Burnum-Johnson, Kristin E; Bartos, Amanda et al. (2015) Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus. J Biol Chem 290:15337-49
Lanekoff, Ingela; Burnum-Johnson, Kristin; Thomas, Mathew et al. (2015) Three-dimensional imaging of lipids and metabolites in tissues by nanospray desorption electrospray ionization mass spectrometry. Anal Bioanal Chem 407:2063-71
Haraguchi, Hirofumi; Saito-Fujita, Tomoko; Hirota, Yasushi et al. (2014) MicroRNA-200a locally attenuates progesterone signaling in the cervix, preventing embryo implantation. Mol Endocrinol 28:1108-17
Cha, Jeeyeon; Bartos, Amanda; Park, Craig et al. (2014) Appropriate crypt formation in the uterus for embryo homing and implantation requires Wnt5a-ROR signaling. Cell Rep 8:382-92
Cha, Jeeyeon; Dey, Sudhansu K (2014) Cadence of procreation: orchestrating embryo-uterine interactions. Semin Cell Dev Biol 34:56-64
Lanekoff, Ingela; Burnum-Johnson, Kristin; Thomas, Mathew et al. (2013) High-speed tandem mass spectrometric in situ imaging by nanospray desorption electrospray ionization mass spectrometry. Anal Chem 85:9596-603

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