Premature Uterine Ageing and Preterm Delivery

子宫早衰和早产

基本信息

批准号：
8733118
负责人：
Jeeyeon Cha
金额：
$ 4.32万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8733118
关键词：
Accounting Address Age Aging-Related Process Animal Model Anti-Inflammatory Agents Anti-Tumor Necrosis Factor Therapy Anti-inflammatory Antibiotics Attenuated Basic Science Birth Cell Culture Techniques Cervical Child Childbirth Clinical Cognitive Decidua Decidual Cell Development Dinoprost Disease Down-Regulation Drops Economic Burden Emotional Etiology Event Fertilization Functional disorder Generations Genes Gestational Age Growth Human Incidence Inflammation Inflammatory Interleukin-1 Labor Onset Lead Lipopolysaccharides Luteolysis Maternal Age Measures Mediating Metabolism Modeling Mus Oral Administration Organ Ovarian Ovulation PTGS2 gene Pathway interactions Play Pregnancy Premature Birth Premature Labor Prevention strategy Preventive Process Progesterone Prostaglandins Protein p53 Proteins Public Health Public Sector Publishing Reporting Research Risk Factors Rodent Model Role Signal Pathway Signal Transduction Sirolimus Study models System Testing Tocolytic Agents Transgenic Mice United States Up-Regulation Uterus Woman Work celecoxib corpus luteum cost disability functional decline implantation inhibitor/antagonist lipoteichoic acid mTOR protein mouse model neonatal death novel strategies premature prevent prostaglandin-F synthase senescence social stillbirth tool treatment strategy

项目摘要

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.

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。定义早产的基本机制将有助于缓解这一毁灭性的全球担忧。无需黄体溶解而自发发生早产的动物模型是研究潜在机制的有力工具，因为它们更接近地模拟人类分娩。利用子宫特异性删除编码 p53 的 Trp53 基因开发了一种新的早产小鼠模型，这些小鼠具有正常的排卵、受精和着床。然而，着床后子宫蜕膜细胞表现出终末分化和衰老相关的生长限制，其中 p21 和 pAKT 水平增加，这两个因素已知参与衰老过程。此外，pAKT 已知可激活 mTOR 通路，该通路与新陈代谢和衰老密切相关。令人惊讶的是，子宫p53缺失和子宫过早衰老会增加早产的发生率。这些发现强调了一个中心假设，即子宫过早衰老在早产中起着核心作用。由于母亲年龄增加是女性早产的危险因素，并且由于衰老小鼠的 p53 功能下降，mTOR 和 p21 信号通路介导的子宫过早衰老可能会促进早产。该假设将得到测试并实现本申请的目标，具体目标如下：(1)确定抑制mTORC1信号传导对子宫p53条件性缺失的小鼠的子宫衰老和早产发生率的影响。这一目标将检验 mTOR（雷帕霉素哺乳动物靶标）信号传导在子宫衰老和早产中发挥关键作用的工作假设。 (2)确定p21缺失叠加p53条件缺失对子宫衰老和早产的影响。这一目标将检验 p21 水平升高导致子宫过早衰老和早产的假设。确定控制早产的独特的、可靶向的途径将对我们对早产病因的理解产生重大影响，并可能导致开发专门针对 mTOR 途径和子宫过早衰老的预防和治疗策略。因此，这项研究为降低早产发生率并减轻全球临床、经济和情感负担的策略奠定了基础。此外，由于这是子宫中 p53 的条件性缺失，因此其他器官中 p53 的缺失可能被证明是一个极好的衰老模型，并可能促进对衰老、衰老和 mTOR 信号传导之间相互作用的进一步了解。