Influences of the prenatal environment on metabolic programming

产前环境对代谢程序的影响

• 批准号: 8052835
• 负责人: KELLIE L. K. TAMASHIRO
• 金额: $ 24.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-10-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052835
• 关键词: Adolescence; Adult; Animal Model; Behavioral; Cardiovascular Diseases; Characteristics; Clinical; Consumption; DNA Methylation; DNA Methylation Regulation; Data; Development; Diabetes Mellitus; Diet; Disease; Endocrine; Environment; Epidemiology; Epigenetic Process; Etiology; Exposure to; Fatty acid glycerol esters; Funding; Genes; Goals; Health; Homeostasis; Human; Hypertension; Insulin Resistance; Intervention; Lactation; Lead; Life Style; Metabolic; Metabolic Diseases; Modification; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Personal Satisfaction; Phenotype; Physiological; Play; Prenatal Nutrition; Prevention strategy; Public Health; Rattus; Risk; Rodent Model; Role; Stress; System; Testing; Time; Work; effective therapy; neuropsychiatry; nutrition; offspring; prenatal; prenatal influence; prenatal stress; programs; research study; response

Obesity Is a major public health problem worldwide and recent work has suggested that exposure to a suboptimal eariy 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 dieL 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-tenn 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 detemiine 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.

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 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， 不良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/或摄入高脂肪饮食是现代人生活方式的特征，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。这项提议的总体目标是描述短期和长期的 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)测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 会加重饮食诱导的肥胖，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。

项目成果

Alterations in DNA methylation of Fkbp5 as a determinant of blood-brain correlation of glucocorticoid exposure.

• DOI: 10.1016/j.psyneuen.2014.03.003
• 发表时间: 2014-06
• 期刊: PSYCHONEUROENDOCRINOLOGY
• 影响因子: 3.7
• 作者: Ewald, Erin R.;Wand, Gary S.;Seifuddin, Fayaz;Yang, Xiaoju;Tamashiro, Kellie L.;Potash, James B.;Zandi, Peter;Lee, Richard S.
• 通讯作者: Lee, Richard S.

Search for common targets of lithium and valproic acid identifies novel epigenetic effects of lithium on the rat leptin receptor gene.

搜索锂和丙戊酸的常见靶标可以确定锂对大鼠瘦素受体基因的新表观遗传作用。

• DOI: 10.1038/tp.2015.90
• 发表时间: 2015-07-14
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Lee RS;Pirooznia M;Guintivano J;Ly M;Ewald ER;Tamashiro KL;Gould TD;Moran TH;Potash JB
• 通讯作者: Potash JB

Environmental influences that alter the stress circuitry.

改变压力电路的环境影响。

• DOI: 10.1055/s-0032-1316326
• 发表时间: 2012
• 期刊: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
• 作者: Ismail,N;Sotomayor-Zarate,R;Bale,TL;Blaustein,JD;Gysling,K;Tamashiro,KLK
• 通讯作者: Tamashiro,KLK