Metabolic mechanisms of uterine contractility in labor

临产时子宫收缩力的代谢机制

• 批准号: 10741953
• 负责人: Antonina I Frolova
• 金额: $ 42.76万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-05 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741953
• 关键词: Adipose tissue; Affect; Age; Agonist; Atopobium vaginae; Automobile Driving; Behavior Therapy; Birth; Body mass index; Cell Separation; Cervical; Cesarean section; Contracts; Data; Defect; Disease; Dose; Energy Metabolism; Europe; Exercise; Failure; Fatty Acids; Fetus; Fiber; Frequencies; Functional disorder; Gene Expression; Glucose; Glucose Transporter; Glycolysis; Goals; Hour; Human; Infant; Knowledge; Labor Dystocia; Lipids; Luteolysis; Metabolic; Metabolic Pathway; Mus; Muscle; Myocardium; Myometrial; Obese Mice; Obesity; Outcome; Oxytocin; Pattern; Phenotype; Practice Management; Pregnancy; Prevalence; Progesterone; Prostaglandins; Research; Resolution; Risk; Risk Factors; Skeletal Muscle; Smooth Muscle; Smooth Muscle Myocytes; Spirometry; Telemetry; Testing; Thinness; Triglycerides; Trimetazidine; Uterine Contraction; Uterus; Vaginal delivery procedure; Weight; Withdrawal; Woman; Work; diet-induced obesity; etomoxir; evidence base; glucose uptake; improved; in vivo; inhibitor; insulin sensitivity; maternal morbidity; maternal obesity; maternal outcome; maternal risk; mother nutrition; mouse model; myometrium; neonatal morbidity; neonatal outcome; obstetric outcomes; obstetrical complication; oxidation; pharmacologic; preference; pup; reproductive; response; uptake; uterine contractility

PROJECT SUMMARY/ABSTRACT Maternal obesity is associated with lower rates of spontaneous labor, slower progress of cervical dilation, and increased risks of labor arrest disorders and induction failure. Additionally, compared to lean women, women with obesity have a nearly three-fold higher rate of cesarean delivery, putting them at increased risk of maternal and neonatal morbidity. While the association between maternal obesity and abnormal labor has been well documented, the mechanisms responsible for this remain unknown. Evidence suggests that obesity causes uterine contractility dysfunction in women. Uterine smooth muscle (myometrium) from women with obesity contracts with less force and frequency than myometrium from normal-weight women and women with obesity require higher doses of oxytocin to achieve a vaginal delivery, suggesting abnormal contractile response. We developed a mouse model of diet-induced obesity that recapitulates the dysfunctional labor patterns seen in women with obesity and can be applied for further mechanistic studies. Here, our objective is to provide a mechanistic understanding of myometrial energy metabolism in control and obese mice during parturition. We focus on energy metabolism because the contractility required for cervical dilation and expulsion of the fetus during labor – lasting for hours to days in humans – places a high energy demand on the myometrium. Our preliminary data also suggest that obese dams have significantly higher lipid (triglyceride and fatty acids) content, increased expression of genes responsible for fatty acid uptake and storage, dysfunctional glycolytic flux, and decreased expression of a key glucose transporter in the myometrium than control dams at term. Thus, our overall hypothesis is that excess fatty acid and triglycerides in the myometrium of obese dams inhibit glucose oxidation, which is required for initiation and progression of early labor. Despite the fact that millions of women deliver an infant each year, we know surprisingly little about how the myometrium meets its energy demands in healthy women or those with obesity. The goals of this project are to (1) define the effects of diet-induced obesity on spontaneous and agonist-induced myometrial contractility and parturition in mice and (2) determine the effects of myometrial energy substrate availability on uterine contractility during labor in the mouse. Our proposed research will provide the necessary mechanistic data to develop pharmacologic and behavioral interventions to optimize myometrial energy storage and utilization during labor. Ultimately, this research may allow us to improve obstetric outcomes for millions of women with obesity.

项目摘要/摘要 孕产妇的肥胖与较低的赞助劳动率有关，宫颈词典的进度较慢， 并增加了劳动逮捕障碍和诱导失败的风险。此外，与精益女性相比 肥胖的妇女的剖宫产率高了近三倍，使她们处于风险增加 母体和新生儿发病率。孕产妇肥胖与劳动异常之间的关联已经 有充分的文献记载，负责此的机制仍然未知。有证据表明这一点 肥胖会导致女性子宫收缩功能障碍。女性的子宫平滑肌（肌层） 与正常体重女性的肌层相比，肥胖合同的力和频率较小， 肥胖的妇女需要更高剂量的氧气才能达到阴道递送，这表明异常 收缩响应。我们开发了一种饮食引起的肥胖症的小鼠模型，该模型概括了 在肥胖女性中看到的功能失调的实验室模式可以应用于进一步的机械研究。 在这里，我们的目标是提供对控制中肌层能量代谢的机械理解 和肥胖的小鼠分娩期间。我们专注于能源代谢，因为 实验室期间胎儿的宫颈扩张和驱逐 - 在人类中持续数小时至数天 - 位置很高 肌层的能量需求。我们的初步数据还表明肥胖的大坝有明显的 较高的脂质（甘油三酸酯和脂肪酸）含量，增加了负责脂肪酸的基因表达 摄取和储存，功能失调的糖酵解通量以及改善钥匙葡萄糖转运蛋白的表达 子宫肌层比对照坝的学期。这就是我们的总体假设是超过脂肪酸和 肥胖水坝肌层中的甘油三酸酯抑制葡萄糖氧化，这是开始和 早期劳动的进展。尽管每年数百万妇女送婴儿，但我们知道 令人惊讶的是，对于健康女性或患有健康女性的能量需求，几乎没有什么 肥胖。该项目的目标是（1）定义饮食引起的肥胖对赞助和的影响 激动剂引起的小鼠的肌定收缩力和分娩，（2）确定肌定测量的影响 小鼠劳动期间子宫收缩性的能量底物可用性。我们提出的研究将 提供必要的机械数据来开发药物和行为干预措施以优化 分娩过程中的肌层能量储能和利用。最终，这项研究可能使我们能够改善 数百万肥胖女性的产科结果。