Premature Uterine Ageing and Preterm Delivery

子宫早衰和早产

• 批准号: 8499175
• 负责人: Jeeyeon Cha
• 金额: $ 4.72万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2015-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499175
• 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

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（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。动物模型自发发展为早产无黄体溶解是研究潜在机制的有力工具，因为它们更接近模拟人类分娩。利用子宫特异性缺失编码p53的Trp53基因建立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，随着p21和pAKT水平的升高，着床后的子宫蜕膜细胞表现出终末分化和衰老相关的生长限制，这两个因素已知参与衰老过程。此外，已知pAKT可以激活mTOR通路，而mTOR通路与代谢和衰老密切相关。令人惊讶的是，子宫p53缺失和子宫早衰增加了早产的发生率。这些发现强调了中心假设，即子宫早衰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，而衰老小鼠p53功能下降，mTOR和p21信号通路介导的子宫早衰可能促进早产。我们将对这一假设进行验证，并实现本应用的目标，具体目的如下：(1)确定mTORC1信号抑制对子宫衰老和条件缺失子宫p53小鼠早产发生率的影响。这一目的将验证mTOR（哺乳动物雷帕霉素靶点）信号在子宫衰老和早产中起关键作用的工作假设。(2)确定p21缺失叠加p53条件缺失对子宫衰老和早产的影响。这一目的将检验p21水平升高导致子宫早衰和早产的工作假设。确定一个独特的、可靶向的控制早产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，本研究为降低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。