Premature Uterine Ageing and Preterm Delivery

描述（由申请人提供）：早产是一个巨大的临床，社会和经济负担。确定早产的基本机制将有助于减轻这一毁灭性的全球关注。自发发生早产而无黄体溶解的动物模型是研究潜在机制的有力工具，因为它们更接近于人类分娩。一种新的小鼠模型的早产使用子宫特异性缺失的Trp53基因编码的p53已经开发出来，这些小鼠具有正常的排卵，受精和植入。然而，着床后子宫蜕膜细胞显示终末分化和衰老相关的生长限制，其中p21和pAKT水平增加，这两种因子已知参与衰老过程。此外，已知pAKT激活mTOR通路，这与代谢和衰老密切相关。令人惊讶的是，子宫p53缺失和子宫过早老化会增加早产的发生率。这些发现强调了子宫早衰在早产中起核心作用的中心假设。由于母亲年龄增加是女性早产的危险因素，并且由于衰老小鼠中p53功能下降，因此mTOR和p21信号通路介导的子宫早衰可能促进早产。将测试该假设并实现本申请的目的，具体目标如下：（1）确定抑制mTORC 1信号传导对子宫p53条件性缺失的小鼠中子宫衰老和早产发生率的影响。这一目标将检验mTOR（哺乳动物雷帕霉素靶蛋白）信号传导在子宫衰老和早产中起关键作用的工作假设。(2)确定p21缺失和p53条件性缺失的叠加对子宫衰老和早产的影响。这一目标将检验工作假设，即p21水平升高导致子宫早衰和早产。确定一个独特的，有针对性的途径控制早产将有显着的影响，我们对早产的病因学的理解，并可能导致专门针对mTOR途径和子宫早衰的预防和治疗策略的发展。因此，这项研究为减少早产发生率和减轻全球临床，经济和情感负担的策略提供了基础。此外，由于这是子宫中p53的条件性缺失，其他器官中p53的缺失可能被证明是衰老的一个很好的模型，并可能促进对衰老，衰老和mTOR信号之间相互作用的进一步理解。

DESCRIPTION (provided by applicant): 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.