Influences of the prenatal environment on metabolic programming

肥胖是世界范围内的一个主要公共健康问题，最近的研究表明，接触 早期环境不理想可能会增加肥胖的风险。流行病学数据显示， 不利的宫内环境会对后代产生长期影响，包括高血压， 心血管疾病、2型糖尿病、肥胖和神经精神疾病。具体地说，产前应激 和/或食用高脂肪饮食，这是现代人类生活方式的特征，已被证明 会导致后代出现肥胖和胰岛素抵抗等代谢紊乱。然而，这些机制 所涉及的人并不是很清楚。这项提案的总体目标是区分短期和长期 产前环境的变化--应激和营养--对行为和生理的影响 子代发育及其可能涉及的神经肽和表观遗传机制 使用的是一个大鼠动物模型。具体目标是：1)确定行为发育的时间进程 以及产前应激引起的内分泌改变。我们还将检验这样一种假设，即产前压力 会加剧饮食导致的肥胖。哺乳期、青春期和成年期的时间点将是 检查以确定表型特征并直接检查可能的机制；2)测试 产前应激、高脂饮食或两者都会导致神经肽系统调节改变的假说 与其他肥胖啮齿动物模型一致的能量平衡；以及3)检验这一假说 产前应激和营养通过表观遗传修饰导致后代肥胖 对能量平衡至关重要的基因的差异DNA甲基化。这些实验将 加强我们对肥胖和代谢性疾病的病因的了解，最终使 针对这种情况开发合理的临床干预措施。这项提议还被构建为 提供丰富多样的培训机会。实习生已经组建了一个指导委员会，将 在进食行为的发展和调节方面提供专门知识(蒂莫西·莫兰博士)，神经生物学 压力和下丘脑-垂体-肾上腺轴的关系(詹姆斯·科尼格博士)以及表观遗传学在 疾病病因学(安德鲁·范伯格博士和詹姆斯·波塔什博士)。这个委员会的指导 与学员之前在行为和分子神经内分泌学方面的工作相结合，将提供 为学员开发多学科研究项目奠定坚实的基础，包括行为学、 生理、细胞/分子和遗传/表观遗传学研究，将促进她向 独立调查员。

Obesity is a major public health problem worldwide and recent work has suggested that exposure to a suboptimal early environment may increase the risk of becoming obese. Epidemiological data show that an unfavorable intrauterine environment has long-term consequences in offspring including hypertension, cardiovascular disease, type 2 diabetes, obesity and neuropsychiatric disease. Specifically, prenatal stress and/or consumption of a high fat diet, characteristics of modern day human lifestyle, have been shown to lead to metabolic disorders such as obesity and insulin resistance in offspring. However, the mechanisms involved are not well understood. The overall goal of this proposal is to characterize the short- and long-term effects of changes inthe prenatal environment - stress andnutrition - onthebehavioral and physiological development of offspring and to explore the possible neuropeptide and epigenetic mechanisms involved using a rat animal model. Specific aims are: 1) To determine the developmental time course of behavioral and endocrine alterations resulting from prenatal stress. We will also test the hypothesis that prenatal stress will accentuate diet-induced obesity. Timepoints during lactation, adolescence, and adulthood will be examined to characterize the phenotype and to direct examination of possible mechanisms; 2) To test the hypothesis that prenatal stress, high fat diet, or both result in alterations in neuropeptide systems regulating energy homeostasis that are consistent with other rodent models of obesity; and 3) To test the hypothesis that prenatal stress and nutrition results in obesity in offspring through epigenetic modifications via differential DNA methylation of genes that are critical to energy homeostasis. These experiments will enhance our understanding of the etiology of obesity and metabolic disease ultimately allowing the development of rational clinical interventions for such conditions. This proposal has also been structured to provide a rich and diverse training opportunity. The trainee has assembled a mentoring committee that will provide expertise in the development and regulation of ingestive behavior (Dr. Timothy Moran), neurobiology of stress and the hypothalamic-pituitary-adrenal axis (Dr. James Koenig) and the role of epigenetics in the etiology of disease (Dr. Andrew Feinberg and Dr. James Potash). The guidance of this committee in conjunction with the trainee's previous work in behavioral and molecular neuroendocrinology, will provide a solid foundation for the trainee to develop a multi-disciplinary program of research including behavioral, physiological, cellular/molecular, and genetic/epigenetic studies that will facilitate her transition to an independent investigator.