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）：心脏病是美国的首要死因，其中缺血性心脏病是发病和死亡的主要原因。然而分子机制在很大程度上仍然难以捉摸。除了其他危险因素外，大型流行病学和动物研究表明，发育过程中胎儿的应激与成年后缺血性心脏病风险增加之间存在明显关联。糖皮质激素在应激反应中发挥着核心作用。我们最近的研究表明，母体/胎儿缺氧导致胎儿心脏中糖皮质激素受体 (GR) mRNA 和蛋白质丰度的减少，这种情况在成年后代中持续存在，这表明发育中的心脏中 GR 基因抑制的子宫表观遗传编程。研究结果表明，糖皮质激素在人类和动物急性心肌缺血和再灌注损伤中具有心脏保护作用，这凸显了心脏中 GR 表达水平降低的病理生理学意义。我们的初步研究表明，缺氧会增加胎儿心脏中 GR 基因启动子的甲基化。 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功能而发生的，但人们对发育中心脏中GR基因表达模式的表观遗传调节及其功能后果知之甚少。拟议的研究将解决我们知识中的这些主要差距，并检验以下假设：发育中的心脏中糖皮质激素受体基因的表观遗传抑制会导致心脏中缺血敏感表型的发育编程。提出了三个具体目标来确定：1）妊娠期间母体/胎儿缺氧会增加启动子甲基化，导致发育中的心脏中 GR 基因抑制；2）缺氧具有直接因果效应，导致 GR 启动子甲基化和基因抑制增强；3 ) 发育中的心脏中缺氧介导的 GR 基因抑制有助于心脏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增进我们对胎儿应激诱导的心脏缺血敏感表型编程的分子机制的了解，从而提高我们对缺血性心脏病病理生理学的理解，而且将提高我们对缺血性心脏病病理生理学的认识。鉴于糖皮质激素在应激反应中发挥着常见和核心作用，还为健康和疾病发育规划广泛领域中调节 GR 基因表达模式的表观遗传机制提供了重要的原创见解。