Maternal Obesity and Origin of Adult Offspring Cardiovascular Disease

摘要 肥胖是一个主要的公共卫生问题，已经达到流行病的程度，在 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)会增加后代患心血管疾病的风险 (CVD)。有证据表明，MO会导致子代心脏重构和功能障碍。然而， 子代脑血管病发生发展的病理生理和分子机制 肥胖母亲的定义仍然很模糊。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齿类、灵长类啮齿类动物中。为了翻译成人类疾病，在 单性早熟物种是必需的。绵羊具有广泛的生理和基因组生活史 数据库使其成为研究成人心血管疾病起源机制的良好模型。我们的初步数据 表明肥胖母羊的胎儿和新生儿皮质醇水平显著升高 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 皮质醇水平升高可能在胎儿、新生儿和成人的病理生理变化中起关键作用。 子孙之心。使用我们的绵羊设施，这可能是美国仅存的设施，用于必要的 对于孕前、孕期和生命过程中后代的维持进行长期研究，我们将测试中心 从妊娠第75天到新生儿通过MO升高胎儿皮质醇水平导致自噬改变的假说 和/或胎儿心脏中的有丝分裂水平，而RBM39在介导这一过程中发挥了关键作用。 与皮质醇受体一起激活。为了检验这一假说，本文提出了两个具体目标。目标1将 评估肥胖母亲胎儿心脏自噬/有丝分裂的变化。目标2将决定角色 RBM39在皮质醇诱导的肥胖母亲胎儿心脏自噬和/或有丝分裂吞噬中的表达。我们的成功 使用这一绵羊模型的研究将为发病的潜在机制提供新的见解 和肥胖母亲后代心血管疾病的发生和发展，使我们能够找到潜在的新靶点 生命后期MO所致心脏重塑和心血管疾病的治疗和预防。

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.