Developmental Programming of Ischemic-Sensitive Phenotype in the Heart

心脏缺血敏感表型的发育编程

• 批准号: 8901692
• 负责人: Lubo Zhang
• 金额: $ 2万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901692
• 关键词: Acute; Address; Adult; Adult Children; Animal Model; Animals; Binding; Biological Models; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cocaine; CpG dinucleotide; Cytosine; DNA Methylation; DNA Methylation Inhibition; Data; Development; Diagnosis; Disease; Elderly; Environment; Epidemiology; Epigenetic Process; Fetal Heart; Fetus; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Glucocorticoid Receptor; Glucocorticoids; Health; Heart; Heart Diseases; Human; Hypoxia; Injury; Knowledge; Malnutrition; Mediating; Messenger RNA; Methylation; Modeling; Modification; Molecular; Morbidity - disease rate; Myocardial; Myocardial Ischemia; Myocardial Reperfusion Injury; Nicotine; Organism; Outcome; Oxygen; Pattern; Phenotype; Physiological; Play; Predisposition; Pregnancy; Preventive; Promoter Regions; Proteins; Rattus; Receptor Gene; Regulation; Reperfusion Injury; Reporting; Repression; Risk; Risk Factors; Role; Series; Stress; Testing; Therapeutic; Time; United States; biological adaptation to stress; cardiovascular disorder risk; fetal; fetus hypoxia; gene repression; hypothalamic-pituitary-adrenal axis; improved; in utero; insight; mortality; offspring; pregnant; prenatal; prenatal stress; programs; promoter; receptor expression; research study; response; tissue culture; transcription factor

DESCRIPTION (provided by applicant): Heart disease is the leading cause of death in the United States, with ischemic heart disease a major cause of morbidity and mortality. Yet the molecular mechanisms remain largely elusive. In addition to other risk factors, large epidemiological and animal studies have shown a clear association of fetal stress during the development with increased risk of ischemic heart disease in adulthood. Glucocorticoids play a center role in the response to stress. Our recent studies demonstrated that maternal/fetal hypoxia resulted in a decrease in glucocorticoid receptor (GR) mRNA and protein abundance in fetal hearts that persisted in adult offspring, suggesting in utero epigenetic programming of GR gene repression in the developing heart. The pathophysiological significance of decreased GR expression levels in the heart is highlighted by the findings that demonstrate cardioprotective effects of glucocorticoids in the acute setting of myocardial ischemia and reperfusion injury both in humans and in animals. Our preliminary studies suggested that hypoxia increased GR gene promoter methylation in fetal hearts. DNA methylation is a chief mechanism in epigenetic modification of gene expression patterns. Although methylation of the GR promoter has been reported to occur as function of physiological regulation of the hypothalamic- pituitary-adrenal axis, little is known about the epigenetic regulation of GR gene expression patterns in the developing heart and its functional consequences. The proposed studies will address these major gaps in our knowledge and test the hypothesis that epigenetic repression of glucocorticoid receptor gene in the developing heart results in developmental programming of ischemic-sensitive phenotype in the heart. Three specific aims are proposed to determine whether: 1) maternal/fetal hypoxia during gestation increases the promoter methylation resulting in GR gene repression in the developing heart, 2) hypoxia has direct causal effects leading to heightened GR promoter methylation and gene repression, and 3) hypoxia-mediated GR gene repression in the developing heart contributes to developmental programming of ischemic-sensitive phenotype in the heart. The overall impact of the proposed studies is that the findings will not only significantly advance our knowledge of molecular mechanisms underlying fetal stress-induced programming of ischemic-sensitive phenotype in the heart and hence improve our understanding of pathophysiology of ischemic heart disease, but they will also provide important original insights into epigenetic mechanisms regulating GR gene expression patterns in a broad field of developmental programming of health and disease, given that glucocorticoids play a common and center role in the stress response.

描述（由申请人提供）：心脏病是美国死亡的主要原因，缺血性心脏病是发病率和死亡率的主要原因。然而，分子机制在很大程度上仍然难以捉摸。除其他危险因素外，大型流行病学和动物研究表明，在发育过程中，胎儿应激与成年后缺血性心脏病的风险增加了。糖皮质激素在应力反应中起着中心作用。我们最近的研究表明，母亲/胎儿缺氧导致胎儿心脏中持续存在的胎儿心脏中糖皮质激素受体（GR）mRNA和蛋白质丰度降低，这表明在发育中的心脏中GR基因抑制作用的子宫遗传学编程。在人类和动物中，糖皮质激素表现出在心肌缺血的急性和再灌注损伤中，糖皮质激素表现出心脏保护作用的发现突显了心脏中GR表达水平降低的病理生理意义。我们的初步研究表明，缺氧增加了胎儿心脏中GR基因启动子甲基化。 DNA甲基化是基因表达模式表观遗传修饰的主要机制。尽管据报道，GR启动子的甲基化是作为下丘脑 - 垂体 - 肾上腺轴的生理调节的功能而发生的，但对于发育中的心脏及其功能后果中GR基因表达模式的表观遗传调节知之甚少。拟议的研究将解决我们知识中的这些主要差距，并检验以下假设：在发育中的心脏中，表观遗传抑制糖皮质激素受体基因会导致心脏中缺血性敏感表型的发育编程。 Three specific aims are proposed to determine whether: 1) maternal/fetal hypoxia during gestation increases the promoter methylation resulting in GR gene repression in the developing heart, 2) hypoxia has direct causal effects leading to heightened GR promoter methylation and gene repression, and 3) hypoxia-mediated GR gene repression in the developing heart contributes to developmental programming of ischemic-sensitive phenotype in the heart.提出的研究的总体影响在于，这些发现不仅会显着提高我们对心脏中缺血性表型的胎儿压力诱导的编程编程的分子机制的了解，从而改善了我们对缺血性心脏病的病理生理学的理解，还将为基因疾病提供了范围的疾病，这些疾病的表达范围是广泛的。糖皮质激素在应力反应中起着共同的中心作用。