Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice

Hirota, Yasushi; Cha, Jeeyeon; Yoshie, Mikihiro; Daikoku, Takiko; Dey, Sudhansu K.

doi:10.1073/pnas.1108180108

Cited by 110 publications

(102 citation statements)

References 35 publications

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“…As reported previously (13,14), administration of either celecoxib or rapamycin rescues spontaneous preterm birth in Trp53 loxP/loxP Pgr Cre/+ females without any apparent adverse effects on the dam or fetuses. These results led us to test whether this treatment would effectively reverse inflammation-exaggerated preterm birth in Trp53 loxP/loxP Pgr Cre/+ females.…”

Section: Rapamycin and P 4 With Or Without Celecoxib Rescue Preterm Bmentioning

confidence: 53%

“…To generate mice with uterine-specific deletion of Trp53, we mated Trp53 loxp/loxP females with males expressing Cre recombinase driven by the Pgr promoter (Pgr Cre/+ ), as previously described (13,14). Trp53 loxP/loxP Pgr Cre/+ females show approximately 50% incidence of spontaneous preterm delivery with dystocia and fetal death compared with floxed littermates showing normal pregnancy outcome; preterm delivery is defined as birth occurring before day 19 of pregnancy (14). To compare the sensitivity of these females to inflammation with respect to preterm birth, we injected TLR4-specific LPS i.p.…”

Section: Trp53 Loxp/loxp Pgrmentioning

confidence: 99%

“…These results led us to speculate that targeting COX2 and/or mTORC1 signaling could prevent preterm birth in this model. Indeed, we were successful in preventing preterm birth in Trp53 loxP/loxP Pgr Cre/+ females by oral gavage of celecoxib, a selective inhibitor of COX2, on day 16 of pregnancy or by inhibition of mTORC1 signaling by a low dose of rapamycin, which attenuated the progression of premature decidual senescence (13,14).…”

Section: Introductionmentioning

confidence: 99%

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Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Cha¹,

Bartos²,

Egashira³

et al. 2013

J. Clin. Invest.

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There are currently more than 15 million preterm births each year. We propose that gene-environment interaction is a major contributor to preterm birth. To address this experimentally, we generated a mouse model with uterine deletion of Trp53, which exhibits approximately 50% incidence of spontaneous preterm birth due to premature decidual senescence with increased mTORC1 activity and COX2 signaling. Here we provide evidence that this predisposition provoked preterm birth in 100% of females exposed to a mild inflammatory insult with LPS, revealing the high significance of gene-environment interactions in preterm birth. More intriguingly, preterm birth was rescued in LPS-treated Trp53-deficient mice when they were treated with a combination of rapamycin (mTORC1 inhibitor) and progesterone (P 4 ), without adverse effects on maternal or fetal health. These results provide evidence for the cooperative contributions of two sites of action (decidua and ovary) toward preterm birth. Moreover, a similar signature of decidual senescence with increased mTORC1 and COX2 signaling was observed in women undergoing preterm birth. Collectively, our findings show that superimposition of inflammation on genetic predisposition results in high incidence of preterm birth and suggest that combined treatment with low doses of rapamycin and P 4 may help reduce the incidence of preterm birth in high-risk women.

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Section: Rapamycin and P 4 With Or Without Celecoxib Rescue Preterm Bmentioning

confidence: 53%

Section: Trp53 Loxp/loxp Pgrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Cha¹,

Bartos²,

Egashira³

et al. 2013

J. Clin. Invest.

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“…Preterm birth has been a global health concern for far too long and the etiology is multifactorial. These risk factors are known to contribute to the cellular senescence process and the genetic evidence proved that p53's downstream, mammalian target of rapamycin complex 1 (mTORC1) signaling plays a key role in uterine senescence and the timing of birth [80]. As aging is a cause of cellular senescence [81,82], and decidual senescence is proved to be associated with premature delivery [79], it is conceivable that uterine senescence imposed by maternal aging carries an increased risk for problematic parturition.…”

Section: Functional Defects In Senescing Endometriummentioning

confidence: 99%

Determinants of uterine aging: lessons from rodent models

Kong

Zhang

Chen

et al. 2012

Sci. China Life Sci.

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The uterus is an indispensable organ for the development of a new life in eutherian mammals. The female mammalian reproductive capacity diminishes with age. In this respect, the senescence of uterine endometrium is convinced to contribute to this failure. This review focuses on the physiological function of the uterus and the related influence of aging mainly in rodent models. A better understanding of the underlying mechanisms governing the process of uterine aging is hoped to generate new strategies to prolong the reproductive lifespan in humans. . More importantly, this phenomenon of continuous decline of fecundity with age has also been confirmed in women over 35 years old [10][11][12]. The success of reproduction in eutherian mammals requires the uterus, a unique organ in the viviparity compared to other organisms ensuring full development of the new life in the maternal body [13]. The endometrial environment of uteri is proved to be one of the critical aspects to determine the reproductive capacity [14] and uterine factor has been proved to be critical for the decline of fecundity in both rodents and humans [4,15]. Most of the available information on uterine aging derives from studies on rats and mice [16]. In these species, life span is short and aging animal model can be easily established. This review focuses on the physiological function of the uterus and the related influence of aging mainly in rodent models. determinants, uterine aging, rodent models

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“…Moreover, these tissue-specific Trp53-deficient mice have increased the incidence of preterm birth and neonatal deaths, partly due to the activation of a prostaglandinmediated pathway (Hirota et al 2010). Low doses of rapamycin, an inhibitor of mTORC1 signaling, can prevent preterm birth in these mice (Hirota et al 2011). mTOR is an important positive regulator of the SASP, and rapamycin can inhibit expression of SASP factors (Laberge et al 2015).…”

Section: Cellular Senescence and Uterine Agingmentioning

confidence: 99%

Positive and negative effects of cellular senescence during female reproductive aging and pregnancy

Velarde

Menon

2016

Journal of Endocrinology

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Cellular senescence is a phenomenon occurring when cells are no longer able to divide even after treatment with growth stimuli. Because senescent cells are typically associated with aging and age-related diseases, cellular senescence is hypothesized to contribute to the age-related decline in reproductive function. However, some data suggest that senescent cells may also be important for normal physiological functions during pregnancy. Herein, we review the positive and negative effects of cellular senescence on female reproductive aging and pregnancy. We discuss how senescent cells accelerate female reproductive aging by promoting the decline in the number of ovarian follicles and increasing complications during pregnancy. We also describe how cellular senescence plays an important role in placental and fetal development as a beneficial process, ensuring proper homeostasis during pregnancy.

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Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice

Cited by 110 publications

References 35 publications

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

Determinants of uterine aging: lessons from rodent models

Positive and negative effects of cellular senescence during female reproductive aging and pregnancy

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