Aberrant Ovine Pancreatic Development in IUGR Fetuses

IUGR 胎儿的羊胰腺发育异常

基本信息

  • 批准号:
    7068396
  • 负责人:
  • 金额:
    $ 12.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-09-20 至 2008-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Intrauterine growth restriction (IUGR) in developed countries accounts for 4-8% of all births and increases perinatal morbidity and mortality. The leading cause of IUGR is decreased nutrient supply to the developing fetus, which results in asymmetric fetal growth due to fetal compensatory mechanisms that maintain viability by sparing critical organs at the expense of others. Epidemiological evidence indicates that IUGR small for gestational age (SGA) infants have a higher susceptibility for adult diseases including non-insulin dependent diabetes mellitus (NIDDM). An explanation for this increased predisposition to NIDDM in adulthood may be fetal programming of structure, physiology, and/or metabolism of pancreatic endocrine cells. Pancreatic beta-cells/islets secrete catabolic and anabolic hormones, which play a central role in regulating metabolism. Therefore, if beta-cell growth and differentiation are reduced by nutrient deprivation, lasting consequences may include decreased beta-cell responsiveness (i.e. decreased insulin secretion capacity) and NIDDM. Additionally, reductions of beta-cell function can be produced by regulatory genes that are structurally changed or epigenetically altered to create a different and lasting functional program. The long-term goal of this project is to determine mechanisms of fetal programming. Specifically, this proposal will examine endocrine pancreas morphometry and development in placental insufficiency IUGR sheep fetuses to characterize this model for fetal pancreatic programming. First we will determine pancreatic developmental stages in the normal fetus during gestation, and subsequently determine deficiencies in beta-cell differentiation and growth that occur in nutrient deprived IUGR fetuses. Additionally, pancreas morphology will be examined for aberrant mesenchymal-epithelial interaction to begin to identify the role of paracrine factors on pancreas endocrine development. Next we will examine gene expression profiles using microarrays to identify regulatory genes that limit pancreas development and/or function by fetal placental insufficiency. We postulate that reductions in fetal beta-cell mass are resulting from decreased beta-cell neogenesis due to limitation in endocrine precursor cells. Gene expression profiles for the developing and IUGR pancreases will be examined to identify regulatory genes involved in programming pancreatic architecture and/or beta-cell function, which lead to reduced insulin secretion responsiveness. These studies will identify mechanisms of fetal programming, be they genetic, structural, or a combination of both, that alter an individual's life-long physiology, providing a firmer foundation for the scientific basis of "fetal origins of adult disease."
描述(由申请人提供): 在发达国家,宫内生长受限(IUGR)占所有新生儿的4-8%,增加了围产儿的发病率和死亡率。IUGR的主要原因是对发育中的胎儿的营养供应减少,这导致胎儿生长不对称,这是由于胎儿的代偿机制,通过牺牲其他器官来保留关键器官来维持生存能力。流行病学证据表明,IUGR小于胎龄儿(SGA)对包括非胰岛素依赖型糖尿病(NIDDM)在内的成人疾病的易感性更高。对成年后NIDDM易感性增加的一个解释可能是胎儿对胰腺内分泌细胞的结构、生理和/或代谢的编程。胰腺β细胞/胰岛分泌分解代谢和合成代谢激素,它们在调节新陈代谢中起着中心作用。因此,如果营养缺乏减少了β细胞的生长和分化,持久的后果可能包括β细胞反应性降低(即胰岛素分泌能力降低)和NIDDM。此外,β细胞功能的降低可以由调控基因产生,这些基因在结构上或表观遗传上发生改变,以创建不同的和持久的功能程序。该项目的长期目标是确定胎儿编程的机制。具体地说,这项建议将检查胎盘功能不全IUGR绵羊胎儿的内分泌胰腺形态测量和发育,以表征该模型用于胎儿胰腺编程。首先,我们将确定正常胎儿在妊娠期间的胰腺发育阶段,然后确定在缺乏营养的IUGR胎儿中出现的β细胞分化和生长缺陷。此外,还将检查胰腺的形态,以了解间充质-上皮细胞的异常相互作用,以确定旁分泌因子在胰腺内分泌发育中的作用。接下来,我们将使用微阵列检查基因表达谱,以确定因胎儿胎盘功能不全而限制胰腺发育和/或功能的调控基因。我们推测,胎儿β细胞质量的减少是由于内分泌前体细胞的限制导致的β细胞新生减少所致。将检查发育中和IUGR胰腺的基因表达谱,以确定参与编程胰腺结构和/或β细胞功能的调节基因,这些基因会导致胰岛素分泌反应性降低。这些研究将确定胎儿程序化的机制,无论是遗传的、结构的,还是两者的组合,这些机制改变了一个人的终身生理,为“成人疾病的胎儿起源”的科学基础提供了更坚实的基础。

项目成果

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SEAN W LIMESAND其他文献

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{{ truncateString('SEAN W LIMESAND', 18)}}的其他基金

Prevention of Placental Insufficiency Improves Beta-Cells Function
预防胎盘功能不全可改善 β 细胞功能
  • 批准号:
    10443326
  • 财政年份:
    2022
  • 资助金额:
    $ 12.97万
  • 项目类别:
Prevention of Placental Insufficiency Improves Beta-Cells Function
预防胎盘功能不全可改善 β 细胞功能
  • 批准号:
    10578797
  • 财政年份:
    2022
  • 资助金额:
    $ 12.97万
  • 项目类别:
Prevention of fetal adrenergic signaling improves metabolic dysfunction in IUGR
预防胎儿肾上腺素能信号传导可改善 IUGR 的代谢功能障碍
  • 批准号:
    9013470
  • 财政年份:
    2009
  • 资助金额:
    $ 12.97万
  • 项目类别:
Impact of Catecholamines to Insulin-Glucose Homeostasis in IUGR Fetuses
儿茶酚胺对 IUGR 胎儿胰岛素-葡萄糖稳态的影响
  • 批准号:
    7802160
  • 财政年份:
    2009
  • 资助金额:
    $ 12.97万
  • 项目类别:
Impact of Catecholamines to Insulin-Glucose Homeostasis in IUGR Fetuses
儿茶酚胺对 IUGR 胎儿胰岛素-葡萄糖稳态的影响
  • 批准号:
    8049119
  • 财政年份:
    2009
  • 资助金额:
    $ 12.97万
  • 项目类别:
Impact of Catecholamines to Insulin-Glucose Homeostasis in IUGR Fetuses
儿茶酚胺对 IUGR 胎儿胰岛素-葡萄糖稳态的影响
  • 批准号:
    8245809
  • 财政年份:
    2009
  • 资助金额:
    $ 12.97万
  • 项目类别:
Impact of Catecholamines to Insulin-Glucose Homeostasis in IUGR Fetuses
儿茶酚胺对 IUGR 胎儿胰岛素-葡萄糖稳态的影响
  • 批准号:
    8443846
  • 财政年份:
    2009
  • 资助金额:
    $ 12.97万
  • 项目类别:
Impact of Catecholamines to Insulin-Glucose Homeostasis in IUGR Fetuses
儿茶酚胺对 IUGR 胎儿胰岛素-葡萄糖稳态的影响
  • 批准号:
    7652919
  • 财政年份:
    2009
  • 资助金额:
    $ 12.97万
  • 项目类别:
Prevention of fetal adrenergic signaling improves metabolic dysfunction in IUGR
预防胎儿肾上腺素能信号传导可改善 IUGR 的代谢功能障碍
  • 批准号:
    8886932
  • 财政年份:
    2009
  • 资助金额:
    $ 12.97万
  • 项目类别:
Aberrant Ovine Pancreatic Development in IUGR Fetuses
IUGR 胎儿的羊胰腺发育异常
  • 批准号:
    6949685
  • 财政年份:
    2004
  • 资助金额:
    $ 12.97万
  • 项目类别:

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