Premature Uterine Ageing and Preterm Delivery

子宫早衰和早产

• 批准号: 8196148
• 负责人: Jeeyeon Cha
• 金额: $ 4.68万
• 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/8196148
• 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. PUBLIC HEALTH RELEVANCE: 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.

描述(申请人提供)：早产是巨大的临床、社会和经济负担。确定早产的基本机制将有助于缓解这种毁灭性的全球担忧。自然发生早产而不发生黄体溶解的动物模型是研究其潜在机制的有力工具，因为它们更接近于人类分娩。一种新的通过子宫特异性缺失编码P53的TrP53基因进行早产的小鼠模型已经被开发出来，这些小鼠具有正常的排卵、受精和着床。然而，植入后的子宫蜕膜细胞表现出终末分化和衰老相关的生长受限，p21和pakt水平升高，这两个已知参与衰老过程的因子。此外，已知PAKT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缺失和子宫过早老化会增加早产的发生率。这些发现强调了一个中心假设，即子宫早衰在早产中起着核心作用。由于孕妇年龄的增加是妇女早产的危险因素，并且由于衰老小鼠的p53功能下降，由mTOR和p21信号通路介导的子宫早衰可能促进早产。这一假说将被验证并实现这一应用的目标，具体目的如下：(1)确定抑制mTORC1信号对子宫衰老和有条件地缺失子宫P53的小鼠早产发生率的影响。这一目标将检验mTOR(哺乳动物雷帕霉素靶标)信号在子宫衰老和早产中发挥关键作用的工作假说。(2)检测p21基因缺失叠加p53基因条件性缺失对子宫衰老和早产的影响。这一目标将检验p21水平升高会导致子宫早衰和早产的工作假说。识别控制早产的独特的、有针对性的途径将对我们理解早产的病因产生重大影响，并可能导致针对mTOR途径和早产的预防和治疗策略的发展。因此，这项研究为降低全球早产发生率和减轻临床、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的有条件缺失，其他器官中的p53缺失可能被证明是一个很好的衰老模型，并可能促进对衰老、衰老和mTOR信号之间相互作用的进一步了解。 公共卫生相关性：这项研究与公共卫生的相关性早产是一个重大的临床、社会和经济负担。在所有新生儿死亡中，早产是近30%的直接原因，每年总计超过100万。此外，许多早产幸存下来的婴儿患有严重的长期残疾。利用转基因小鼠模型，这项拟议的研究将检验这样一种假设，即哺乳动物雷帕霉素靶标(MTOR)信号升高导致的子宫早衰是早产的主要原因，抑制这一信号将逆转这一衰弱事件。