Developmental Programming of Ischemic-Sensitive Phenotype in the Heart

心脏缺血敏感表型的发育编程

基本信息

  • 批准号:
    8901692
  • 负责人:
  • 金额:
    $ 2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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,发育过程中的胎儿压力与成年后缺血性心脏病风险增加有明显关联。糖皮质激素在应激反应中起着核心作用。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和蛋白丰度的降低,并在成年后代中持续存在,这表明GR基因抑制在发育中的心脏中存在子宫表观遗传编程。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,从而强调了心脏中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。虽然GR启动子的甲基化已被报道为下丘脑-垂体-肾上腺轴生理调节的功能,但对发育中的心脏中GR基因表达模式的表观遗传调控及其功能后果知之甚少。提出的研究将解决这些主要的知识空白,并验证在心脏发育中糖皮质激素受体基因的表观遗传抑制导致心脏缺血敏感表型的发育规划的假设。我们提出了三个具体的目的来确定:1)妊娠期间母体/胎儿缺氧是否增加启动子甲基化导致发育中的心脏中GR基因抑制;2)缺氧是否有直接的因果效应导致GR启动子甲基化和基因抑制升高;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。这些研究的总体影响是,这些发现不仅将显著推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认识,从而提高我们对缺血性心脏病病理生理学的理解,而且还将为在健康和疾病发育编程的广泛领域中调节GR基因表达模式的表观遗传机制提供重要的原始见解。鉴于糖皮质激素在应激反应中起着共同的中心作用。

项目成果

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Lubo Zhang其他文献

Lubo Zhang的其他文献

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{{ truncateString('Lubo Zhang', 18)}}的其他基金

Uterine Arterial Spontaneous Transient Outward Currents in Pregnancy
妊娠期子宫动脉自发瞬时外向电流
  • 批准号:
    9360213
  • 财政年份:
    2017
  • 资助金额:
    $ 2万
  • 项目类别:
Core B - Technical
核心 B - 技术
  • 批准号:
    9072342
  • 财政年份:
    2016
  • 资助金额:
    $ 2万
  • 项目类别:
Gestational Hypoxia and Developmental Plasticity
妊娠缺氧与发育可塑性
  • 批准号:
    9241396
  • 财政年份:
    2016
  • 资助金额:
    $ 2万
  • 项目类别:
Uterine Vascular Adaptation to Pregnancy and Chronic Hypoxia
子宫血管对妊娠的适应和慢性缺氧
  • 批准号:
    9072343
  • 财政年份:
    2016
  • 资助金额:
    $ 2万
  • 项目类别:
Core A - Administrative
核心 A - 行政
  • 批准号:
    9072341
  • 财政年份:
    2016
  • 资助金额:
    $ 2万
  • 项目类别:
Epigenetic mechanisms of uterine vascular adaptation to pregnancy and hypoxia
子宫血管适应妊娠和缺氧的表观遗传机制
  • 批准号:
    9242047
  • 财政年份:
    2015
  • 资助金额:
    $ 2万
  • 项目类别:
DNA Demethylation and BKca Channel Expression and Function in Uterine Arteries
子宫动脉中 DNA 去甲基化和 BKca 通道表达和功能
  • 批准号:
    9020248
  • 财政年份:
    2015
  • 资助金额:
    $ 2万
  • 项目类别:
DNA Demethylation and BKca Channel Expression and Function in Uterine Arteries
子宫动脉中 DNA 去甲基化和 BKca 通道表达和功能
  • 批准号:
    8858032
  • 财政年份:
    2015
  • 资助金额:
    $ 2万
  • 项目类别:
Epigenetic mechanisms of uterine vascular adaptation to pregnancy and hypoxia
子宫血管适应妊娠和缺氧的表观遗传机制
  • 批准号:
    9096200
  • 财政年份:
    2015
  • 资助金额:
    $ 2万
  • 项目类别:
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:
    9186002
  • 财政年份:
    2013
  • 资助金额:
    $ 2万
  • 项目类别:

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