Influences of the prenatal environment on metabolic programming

产前环境对代谢程序的影响

• 批准号: 7223832
• 负责人: KELLIE L. K. TAMASHIRO
• 金额: $ 6.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7223832
• 关键词: Adolescence; Adult; Affect; Animal Model; Appetitive Behavior; Behavioral; Birth; Body Weight; Cardiovascular Diseases; Characteristics; Clinical; Condition; Consumption; DNA Methylation; Data; Development; Diet; Disease; Endocrine; Environment; Epigenetic Process; Etiology; Exposure to; Fatty acid glycerol esters; Feeding behaviors; Fetus; Foundations; Genes; Goals; Health; Homeostasis; Human; Hypertension; Insulin Resistance; Intervention; Lactation; Lead; Life Style; Long-Term Effects; Mentors; Metabolic; Metabolic Diseases; Methylation; Modeling; Modification; Molecular; Molecular Genetics; Neonatal; Neurobiology; Neuroendocrinology; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Phenotype; Physiological; Potassium Hydroxide; Pregnancy; Public Health; Rattus; Regulation; Research; Research Personnel; Risk; Rodent Model; Role; Solid; Stress; Structure; System; Testing; Time; Training; Weaning; Work; day; feeding; hypothalamic-pituitary-adrenal axis; neuropsychiatry; nutrition; prenatal; prenatal influence; prenatal stress; prevent; programs; research study; response

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.

描述（由申请人提供）：肥胖是世界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。流行病学数据表明，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。具体而言，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）已被证明会导致后代代谢紊乱，例如肥胖和胰岛素抵抗。然而，所涉及的机制尚不清楚。该提案的总体目标是描述产前环境（压力和营养）变化对后代行为和生理发育的短期和长期影响，并利用大鼠动物探索可能涉及的神经肽和表观遗传机制模型。具体目标是： 1) 确定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剧饮食引起的肥胖的假设。将检查哺乳期、青春期和成年期间的时间点，以表征表型并直接检查可能的机制； 2) 检验以下假设：产前应激、高脂肪饮食或两者都会导致调节能量稳态的神经肽系统发生改变，这与其他肥胖啮齿动物模型一致； 3) 检验以下假设：产前压力和营养通过对能量稳态至关重要的基因的差异 DNA 甲基化进行表观遗传修饰，从而导致后代肥胖。这些实验将增强我们对肥胖和代谢疾病病因的理解，最终为此类疾病制定合理的临床干预措施。该提案的结构还旨在提供丰富多样的培训机会。学员组建了一个指导委员会，该委员会将提供以下方面的专业知识：摄入行为的发展和调节（蒂莫西·莫兰博士）、压力神经生物学和下丘脑-垂体-肾上腺轴（詹姆斯·科尼格博士）以及表观遗传学在饮食行为中的作用。疾病病因学（Andrew Feinberg 博士和 James Potash 博士）。该委员会的指导结合受训者之前在行为和分子神经内分泌学方面的工作，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/表观遗传学研究，将有助于她过渡为独立调查员。