Influences of the prenatal environment on metabolic programming

描述（由申请人提供）：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，暴露于次优的早期环境可能会增加肥胖的风险。流行病学数据显示，不利的宫内环境对后代有长期影响，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，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）已显示导致后代的代谢紊乱，例如肥胖和胰岛素抵抗。然而，所涉及的机制并不清楚。本提案的总体目标是描述产前环境变化（压力和营养）对后代行为和生理发育的短期和长期影响，并探索可能的神经肽和表观遗传机制。具体目标是：1）确定由产前应激引起的行为和内分泌改变的发育时间过程。我们还将检验产前压力会加重饮食引起的肥胖的假设。将检查哺乳期、青春期和成年期的时间点，以表征表型并直接检查可能的机制; 2）检验产前应激、高脂肪饮食或两者导致调节能量稳态的神经肽系统改变的假设，所述改变与其他啮齿动物肥胖模型一致;和3）检验产前压力和营养通过表观遗传修饰导致后代肥胖的假设，所述表观遗传修饰经由对能量稳态至关重要的基因的差异DNA甲基化。这些实验将增强我们对肥胖和代谢性疾病病因学的理解，最终允许为此类疾病制定合理的临床干预措施。这项建议的结构也是为了提供丰富多样的培训机会。培训生已经组建了一个指导委员会，将提供以下方面的专业知识：摄食行为的发展和调节（Timothy Moran博士）、应激神经生物学和下丘脑-垂体-肾上腺轴（James Koenig博士）以及表观遗传学在疾病病因学中的作用（Andrew Feinberg博士和James Potash博士）。该委员会的指导与受训者以前在行为和分子神经内分泌学方面的工作相结合，将为受训者制定多学科研究计划提供坚实的基础，包括行为，生理，细胞/分子和遗传/表观遗传研究，这将有助于她过渡到独立研究者。

DESCRIPTION (provided by applicant): 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 in the prenatal environment - stress and nutrition - on the behavioral 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. Time points 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.