Influences of the prenatal environment on metabolic programming

肥胖是全球范围内的一个主要公共卫生问题，最近的研究表明， 不理想的早期环境可能会增加肥胖的风险。流行病学数据显示， 不利的子宫内环境对后代具有长期后果，包括高血压， 心血管疾病、2型糖尿病、肥胖症和神经精神疾病。特别是产前压力 和/或高脂肪饮食的消耗，现代人类生活方式的特征，已经被证明， 导致后代代谢紊乱如肥胖和胰岛素抵抗。然而，机制 所涉及的问题并没有得到很好的理解。本提案的总体目标是， 产前环境的变化-压力和营养-对行为和生理的影响 并探讨可能的神经肽和表观遗传机制参与 使用大鼠动物模型。具体目标是：1）确定行为的发展时间进程， 以及产前压力导致的内分泌改变我们还将检验产前压力 会加重饮食导致的肥胖哺乳期、青春期和成年期的时间点将是 检查以表征表型并直接检查可能的机制; 2）测试 假设产前压力，高脂肪饮食，或两者都导致神经肽系统调节的改变， 能量稳态与其他啮齿动物肥胖模型一致;和3）为了检验假设 产前压力和营养通过表观遗传修饰， 差异DNA甲基化的基因是至关重要的能量稳态。这些实验将 提高我们对肥胖和代谢疾病病因学的理解， 为此类疾病制定合理的临床干预措施。这一建议的结构也是为了 提供丰富多样的培训机会。受训者已经组建了一个指导委员会， 在摄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（詹姆斯·凯尼格博士）以及表观遗传学在 疾病的病因（安德鲁·范伯格博士和詹姆斯·Potash博士）。该委员会的指导， 结合学员以前在行为和分子神经内分泌学方面的工作，将提供一个 为学员发展多学科研究计划奠定坚实的基础， 生理，细胞/分子和遗传/表观遗传研究，将促进她的过渡到一个 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.