Aberrant Ovine Pancreatic Development in IUGR Fetuses

描述（由申请人提供）： 在发达国家，宫内生长受限（IUGR）占所有出生的4-8%，并增加了围产期发病率和死亡率。IUGR的主要原因是发育中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，小于胎龄儿（SGA）的IUGR婴儿对包括非胰岛素依赖型糖尿病（NIDDM）在内的成人疾病具有较高的易感性。对成年期NIDDM易感性增加的解释可能是胰腺内分泌细胞的结构、生理和/或代谢的胎儿编程。胰腺β细胞/胰岛分泌分解代谢和合成代谢激素，其在调节代谢中起核心作用。因此，如果β细胞生长和分化因营养缺乏而减少，则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节基因产生，所述调节基因在结构上改变或表观遗传学上改变以产生不同且持久的功能程序。该项目的长期目标是确定胎儿编程的机制。具体而言，本建议将检查内分泌胰腺形态和胎盘功能不全IUGR羊胎儿的发展，以表征胎儿胰腺编程的模型。首先，我们将确定胰腺发育阶段在正常胎儿在怀孕期间，并随后确定缺陷β细胞分化和生长发生在营养缺乏IUGR胎儿。此外，将检查胰腺形态学中异常间质-上皮相互作用，以开始确定旁分泌因子对胰腺内分泌发育的作用。接下来，我们将使用微阵列检测基因表达谱，以确定胎儿胎盘功能不全限制胰腺发育和/或功能的调控基因。我们推测胎儿β细胞量的减少是由于内分泌前体细胞的限制导致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，以鉴定参与编程胰腺结构和/或β细胞功能的调控基因，其导致胰岛素分泌反应性降低。这些研究将确定胎儿编程的机制，无论是遗传的，结构的，还是两者的结合，这些机制改变了个体的终身生理学，为“成人疾病的胎儿起源”的科学基础提供了更坚实的基础。"

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."