Maternal Obesity and Origin of Adult Offspring Cardiovascular Disease

总结 肥胖是一个主要的公共卫生问题，已达到流行病的比例， 美国的女性。在世界范围内，超过30%的孕妇肥胖。人类流行病学 研究表明，母亲肥胖（MO）会增加后代日后患心血管疾病的风险， （CVD）。有证据表明，MO导致后代心脏重塑和功能障碍。但 病理生理学和分子机制强调了CVD的发生和发展的后代， 肥胖母亲的定义仍然不明确。大多数关于MO对发育挑战的不利影响的研究， 生活过程的结果是在多胎的，altricial啮齿动物。对于人类疾病的翻译， 需要单性早熟的物种。绵羊具有广泛的生命历程生理和基因组 数据库，为成人CVD发病机制的研究提供了良好的模型。我们的初步数据 表明，皮质醇水平显着升高，胎儿和新生儿的肥胖母羊相比， 控制母羊。来自许多独立实验室的许多物种的令人信服的证据表明， 皮质醇水平升高在胎儿、新生儿和成人的病理生理变化中起重要作用 孩子的心使用我们的羊设施，这可能是唯一剩下的美国设施，为必要的 对孕前、孕期及子代生命过程的维持进行长期研究，我们将检测中枢 从妊娠75天到新生儿MO升高胎儿皮质醇水平导致自噬改变的假说 和/或线粒体自噬水平，RBM 39在介导这一过程中起着关键作用， 与皮质醇受体一起沿着激活。提出了两个具体的目标来检验这一假设。目标1将 评估肥胖母亲胎儿心脏中自噬/线粒体自噬的变化。目标2将决定作用 RBM 39在肥胖母亲胎儿心脏中皮质醇诱导的自噬和/或线粒体自噬中的作用。的成功 使用这种MO绵羊模型的研究将为发病的潜在机制提供新的见解 以及肥胖母亲后代CVD的发生，并使我们能够找到潜在的新靶点， 治疗和预防MO诱导的心脏重塑和以后的CVD。

SUMMARY Obesity is a major public health problem which has reached epidemic proportions with rates of about 36% for women in the United States. Worldwide, over 30% of pregnant women are obese. Human epidemiological studies have shown that maternal obesity (MO) increases risks of offspring later life cardiovascular disease (CVD). Evidence suggests that MO leads to offspring cardiac remodeling and dysfunction. However, the pathophysiological and molecular mechanisms underscoring the onset and development of CVD in offspring of obese mothers remain poorly defined. Most studies of adverse effects of MO on developmental challenges and life course outcomes are in polytocous, altricial rodents. For translation to human disease, studies in monotocous precocial species are required. Sheep have an extensive life course physiological and genomic database making them good models for studies of mechanisms of origins of adult CVD. Our preliminary data indicates that cortisol levels are significantly elevated in fetuses and newborns of obese ewes by comparing to control ewes. The compelling body of evidence in many species from many independent laboratories showed that the elevated cortisol level could play a key role in pathophysiological changes of fetal, neonatal and adult offspring heart. Using our sheep facilities which are probably the only remaining USA facility for the necessary pre-pregnancy, pregnancy and life course offspring maintenance for long-term study, we will test the central hypothesis that elevated fetal cortisol level by MO from gestation day75 to newborn leads to altered autophagy and/or mitophagy level in fetal hearts, and RBM39 plays a critical role in mediating this process through co- activation along with cortisol receptors. Two specific aims are proposed to test the hypothesis. Aim 1 will assess autophagy/mitophagy changes in the heart of fetuses of obese mothers. Aim 2 will determine the role of RBM39 in cortisol-induced autophagy and/or mitophagy in fetal hearts of obese mothers. The success of our research using this MO sheep model will provide novel insights into the underlying mechanisms in the onset and development of CVD in offspring of obese mothers, and enable us to find potential new targets for the treatment and prevention of MO-induced cardiac remodeling and CVD later on in life.