Maternal Obesity and Weight Change in Neurobehavioral Development

自闭症谱系障碍(ASD)和发育迟缓(DD)的非遗传危险因素包括母亲 与代谢失调有关的疾病，最明显的是孕前肥胖、过度妊娠 体重增加，以及与代谢健康不良相关的并发症，包括慢性和妊娠形式 高血压、糖尿病和血脂异常。肥胖症在美国已经达到流行的程度，还有更多的人 超过一半的孕妇超重或肥胖。种族和社会经济差异是巨大的。这个 拟议的研究计划将探索母亲肥胖的生理特征，这些特征可能涉及 非人灵长类动物模型中的神经发育妥协。我们将比较炎症性和 肥胖和正常体重母亲妊娠环境的代谢变化，以及组织学和 对胎盘和婴儿大脑进行表观遗传修饰。此外，我们将评估两项措施的有效性 孕妇干预策略、孕期体重维持和药物的日常使用 孕期服用普伐他汀逆转母体肥胖对母体和胎盘的影响 环境。体重管理已被医学研究所和 美国产科医生和妇科医生会议管理妊娠期肥胖，以及 普伐他汀的药理特性为其用于预防全身、 母体肥胖对胎盘和胎儿的影响。这一建议力求充分利用 利用妊娠晚期恒河猴模型所固有的资源来解决这一严重的临床问题 对公共卫生造成重大影响。我们的跨学科团队将调查人员的专业知识与 在孕产妇健康和胎儿发育、生殖生理学、营养、 免疫学、表观遗传学、代谢组学、脂组学、生物统计学和神经发育 非人灵长类动物。该项目的具体目标将：1)探索母体的生理效应 导致神经发育障碍的肥胖和2)决定了两种干预策略 将防止母体肥胖的影响。这些研究的结果将具有直接的翻译价值 告知妇女和她们的保健提供者母体肥胖对发育中的大脑和意志的风险 提供有关预防方案的信息，以帮助肥胖妇女及其医疗保健提供者降低患肥胖症的风险 他们的孩子。

Non-heritable risk factors for autism spectrum disorder (ASD) and developmental delay (DD) include maternal conditions associated with metabolic dysregulation, most notably pre-pregnancy obesity, excessive gestational weight gain, and complications associated with poor metabolic health, including chronic and gestational forms of hypertension, diabetes and dyslipidemia. Obesity has reached epidemic proportions in the U.S., with more than half of pregnant women overweight or obese. Racial and socioeconomic disparities are profound. The proposed research plan will explore physiological characteristics of maternal obesity that may be involved in neurodevelopmental compromise in a non-human primate model. We will compare inflammatory and metabolic changes to the gestational milieu in obese and normal-weighted mothers, as well as histologic and epigenetic modifications to the placenta and infant brain. Additionally, we will evaluate the effectiveness of two maternal intervention strategies, gestational weight maintenance and daily administration of the pharmacologic agent pravastatin through pregnancy, in reversing the effects of maternal obesity on the maternal and placental environments. Weight management has been recommended by both the Institute of Medicine and the American Congress of Obstetricians and Gynecologists for management of obesity in pregnancy, and the pharmacological properties of pravastatin provide biological plausibility for its use in preventing the systemic, placental and fetal consequences of maternal obesity. This proposal strives to utilize fully the unique resources inherent in the third trimester rhesus monkey model to address this serious clinical problem with substantial public health impact. Our interdisciplinary team weaves the expertise of investigators with extensive collaborative experience in maternal health and fetal development, reproductive physiology, nutrition, immunology, epigenetics, metabolomics, lipomics, biostatistics and neurodevelopment in both humans and non-human primates. The specific aims of the project will: 1) explore the physiologic effects of maternal obesity that underlie neurodevelopmental impairment and 2) determine whether two interventional strategies will prevent the effects of maternal obesity. The outcome of these studies will have direct translational value by informing women and their health providers of the risks of maternal obesity to the developing brain and will provide information on preventive options to help obese women and their health care providers lessen risk for their babies.