Metabolic mechanisms of uterine contractility in labor

临产时子宫收缩力的代谢机制

基本信息

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
项目类别：
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

项目摘要

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/摘要孕产妇肥胖与自发性劳动率，宫颈扩张进展较慢有关，与精益妇女相比，增加了劳动逮捕障碍的风险肥胖女性的剖宫产率近三倍，使风险增加孕产妇和新生儿的病态。有充分的记录，负责此的机制仍然被关注。肥胖导致女性子宫功能障碍。与正常体重女性相比，与终身和自由的寿命更少，肥胖的妇女需要更高剂量的催产素才能达到阴道递送，这表明异常收缩的响应。肥胖症中看到的功能失调的劳动模式可以用于机械研究。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在局部时期，我们专注于能量代谢分娩过程中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。较高的脂质（甘油三酸酯和脂肪酸）含量增加，脂肪酸基因反应的表达增加摄取和储存，功能失调的糖酵解通量以及关键葡萄糖转运的表达降低子宫肌术比对照乳头的术语，因此，我们的总体假设是肥胖乳液子宫内甘油三酸酯抑制葡萄糖氧化，这是起始必需的早期的劳动进展。令人惊讶的是，在健康女性或患有的女性中，肌层如何满足其能量需求。肥胖。激动剂诱导的小鼠肌层收缩性和部分性，（2）确定肌层的影响小鼠劳动期间子宫收缩性的能量底物可用性。提供必要的机械数据来开发药理学和行为国际以优化在劳动期间，肌层储能和利用率最终使我们能够改善数百万肥胖女性的产科结果。