Effects of maternal cortisol on perinatal cardiac metabolism and function

项目摘要 皮质醇是包括心脏在内的胎儿器官成熟的调节剂。母体高皮质醇血症或应激 似乎增加了足月死胎的风险，并改变了胎儿心脏的生长。在动物模型中， 怀孕后期母体皮质醇升高，模仿轻度但慢性的压力，我们发现了一个惊人的 死胎增加和胎儿心脏基因表达的变化表明葡萄糖的变化 代谢、线粒体功能和能量可用性。数据支持这样的假设， TCA循环活性以及线粒体数量和功能的下调。拟议的研究将测试 总体假设，胎儿皮质醇的改变改变心脏代谢，功能和重塑， 妊娠，并最终导致胎儿心脏功能障碍，包括结构和功能的变化， 导致分娩和分娩期间或产后即刻的不良事件。我们将测试 应用无线电遥测技术在控制分娩过程中胎儿心脏病理生理学的进行性变化 监测胎儿主动脉压和ECG，超声分析胎儿心脏尺寸和功能，以及 转录组学、代谢组学、组织病理学和生物化学方法来研究心脏 结构和代谢。我们将检验以下假设：正常的葡萄糖代谢途径被破坏 和乳酸代谢和线粒体功能的丧失，这将反映在线粒体的变化， 呼吸测量、基因表达和代谢组学。我们将检验一个假设 心脏结构和功能的病理生理变化，将通过心室肌的变化反映出来。 通过超声心动图确定的尺寸和功能，以及主动脉压和ECG的变化。 我们还将使用13 C葡萄糖通量和13 C葡萄糖的鉴定来测试心脏对葡萄糖利用的改变。 血浆和心脏组织中的葡萄糖异构体。我们将进一步检验假设， 心脏代谢和线粒体是心脏代谢变化和心电图变化的基础， 施用二氯乙酸盐，一种增加丙酮酸盐活性的小分子治疗剂， 脱氢酶复合物，其是TCA循环活性所需的。DCA将在 分娩，在我们的模型中ECG异常变得明显的时间。DCA用于人类， 线粒体疾病，包括患有乳酸酸中毒的儿童，这项研究的数据可能会 提供一种新生儿急性抢救的治疗方法。

Project Summary Cortisol is a regulator of maturation of fetal organs, including the heart. Maternal hypercortisolemia or stress appears to increase the risk of stillbirth at term and alter growth of the fetal heart. In an animal model with elevated maternal cortisol in late gestation, mimicking mild but chronic stress, we have found a striking increase in stillbirth and changes in gene expression in the fetal heart suggesting changes in glucose metabolism, mitochondrial function, and energy availability. The data support the hypothesis that there is downregulation of TCA cycle activity and mitochondrial number and function. The proposed studies will test the overarching hypothesis that alterations in fetal cortisol alter cardiac metabolism, function and remodeling in late gestation, and ultimately lead to fetal cardiac dysfunction, including both structural and functional changes, that result in adverse events during labor and delivery or in the immediate postnatal period. We will test for progressive changes in pathophysiology in the fetal heart during controlled labor using radiotelemetric monitoring of fetal aortic pressure and ECG, ultrasound analysis of fetal heart dimensions and function, and transcriptomic, metabolomic, histopathologic, and biochemical approaches to investigate changes in cardiac structure and metabolism. We will test the hypothesis that there is disruption of normal pathways for glucose and lactate metabolism and loss of mitochondrial function that will be reflected in changes in mitochondrial respirometry, gene expression and metabolomics. We will test the hypothesis that there will be pathophysiologic changes in cardiac structure and function that will be reflected by changes in ventricular dimensions and function identified by echocardiography, as well as alterations in aortic pressure, and in ECG. We will also test for alterations in glucose utilization by the heart using 13C glucose flux and identification of 13C glucose isoptomers in plasma and in the heart tissue. We will further test the hypothesis that changes in cardiac metabolism and mitochondria underlie changes in cardiac metabolism and ECG changes using administration of dichloroacetate, a small molecule therapeutic that increases activity of the pyruvate dehydrogenase complex, which is required for TCA cycle activity. DCA will be administered acutely during labor, the time at which the abnormalities in ECG become evident in our model. DCA is used in humans with mitochondrial diseases, including children with lactic acidosis, and the data from this study would potentially provide a therapeutic method for acute rescue of neonates.