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: 8962160
• 负责人: Lubo Zhang
• 金额: $ 45.19万
• 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/8962160
• 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; 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; epigenetic regulation; fetal; fetus hypoxia; gene repression; hypothalamic-pituitary-adrenal axis; improved; in utero; insight; methylation pattern; 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）：心脏病是美国的主要死因，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。除了其他风险因素外，大型流行病学和动物研究表明，发育期间的胎儿应激与成年后缺血性心脏病风险增加有明确的关联。糖皮质激素在应激反应中起核心作用。我们最近的研究表明，母亲/胎儿缺氧导致胎儿心脏中糖皮质激素受体（GR）mRNA和蛋白丰度的减少，并持续在成年后代中，这表明在子宫内发育中的心脏中GR基因抑制的表观遗传编程。心脏中GR表达水平降低的病理生理学意义通过证明糖皮质激素在人类和动物心肌缺血和再灌注损伤的急性环境中的心脏保护作用的发现而突出。我们的初步研究表明，缺氧增加胎儿心脏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。虽然已经报道了GR启动子的甲基化作为下丘脑-垂体-肾上腺轴的生理调节的功能而发生，但是关于发育中的心脏中GR基因表达模式的表观遗传调节及其功能后果知之甚少。拟议的研究将解决这些主要差距，我们的知识和测试的假设，即表观遗传抑制糖皮质激素受体基因在发育中的心脏缺血敏感表型的发育编程的结果。提出了三个具体目标来确定：1）妊娠期间母体/胎儿缺氧是否增加了启动子甲基化，从而导致发育中心脏中的GR基因抑制，2）缺氧是否具有直接因果效应，从而导致GR启动子甲基化和基因抑制增加，以及3）发育中心脏中缺氧介导的GR基因抑制是否有助于心脏中缺血敏感表型的发育编程。拟议研究的总体影响是，这些发现不仅将显着推进我们对胎儿应激诱导心脏缺血敏感表型编程的分子机制的认识，从而提高我们对缺血性心脏病病理生理学的理解，但它们也将为调节GR基因表达模式的表观遗传机制提供重要的原始见解，健康与疾病，因为糖皮质激素在压力反应中发挥着常见的核心作用。