Nutrient Coordination of Pancreatic Vasculature and Beta-Cells

描述(由申请人提供)：在发达国家，宫内生长受限(IUGR)影响所有妊娠的4-8%；最常见的原因是胎盘功能不全和胎儿营养供应减少。为了生存，胎儿以促进有限能量供应的最有效利用的方式进行适应。胰岛β细胞在这种适应中起着关键作用。β细胞以一种营养调节的方式分泌胰岛素，从而刺激胎儿生长。因此，胰岛β细胞是使生长速度与营养供应相匹配的最重要的胎儿细胞类型之一。关于严重的人类IUGR中胰岛素分泌减少的机制，最好的证据是胰腺β细胞数量的减少。实验证据表明，这些适应不是简单地通过向生长受限的胎儿提供更多的营养来克服的。因此，治疗IUGR以提高胎儿生长率的任何希望都必须结合增加胎儿营养供应和β细胞胰岛素分泌的策略。此外，如果这些限制胎儿β细胞数量和胰岛素分泌的适应持续到成年，它们可能会导致以前生长受限的成年人患2型糖尿病的风险更高。新的证据表明，胰腺血管生成和血管生成对于维持正常的胰岛β细胞群和胰岛素分泌的重要性。与严重的人类IUGR一致，我们的初步数据显示，在IUGR胎盘功能不全模型中，胰腺血管减少。因此，这项建议的长期目标是确定胎儿营养供应如何调节胰腺血管和血管生成。该项目的总体假设是胰腺血管内皮生长因子A(VEGFA)和血管受到胎儿葡萄糖和氨基酸供应的正向调节，IUGR时胰腺β细胞发育不良是由于营养和胰岛素刺激的血管减少所致。我们将使用体内和体外研究的独特组合来实现这些目标。这包括对正常生长和IUGR胎儿的胎儿营养供应进行实验操作，结合胰腺和胰岛血管、VEGFA和其他血管生成生长因子、β细胞功能、质量和复制的分析，以及分离胎儿胰岛和胰岛来源的内皮细胞进行功能分析。除了胎儿胰腺和β细胞对营养操作的功能和发育反应外，该项目还将提供有关IUGR胎儿对增加的营养供应的总体反应的重要信息，这将对胎儿医学领域以及最终开发针对IUGR的胎儿干预措施以及预防先前生长受限的成人糖尿病具有重要意义。最后，这些项目将显著增加我们对β细胞复制和质量的调节以及内皮细胞和β细胞之间的相互作用的理解，从而为β细胞生物学领域提供重要的进展。

DESCRIPTION (provided by applicant): Intrauterine growth restriction (IUGR) affects 4-8% of all pregnancies in developed countries; the most common etiology being placental insufficiency and decreased fetal nutrient supply. In order to survive, the fetus adapts in ways which promote the most efficient use of a limited energy supply. Pancreatic beta-cells are key in this adaptation. The beta-cell secretes insulin, which stimulates fetal growth, in a nutrient regulated fashion. Therefore, the pancreatic beta-cell is one of the most important fetal cell types for matching growth rates to nutrient supply. The best evidence regarding the mechanism of decreased insulin secretion in severe human IUGR is a decrease in the pancreatic beta-cell population. Experimental evidence suggests that these adaptations cannot be overcome simply by providing increased nutrients to the growth restricted fetus. Therefore, any hope of treating IUGR to improve fetal growth rates will have to combine strategies to increase fetal nutrient delivery and beta-cell insulin secretion. Additionally, if these adaptations which limit the fetal beta-cell population and insulin secretion persist into adulthood they can contribute to the higher risk of type 2 diabetes mellitus in previously growth restricted adults. New evidence is emerging which shows the importance of the pancreatic vasculature and angiogenesis for maintenance of the normal beta-cell population and insulin secretion. Consistent with severe human IUGR, our preliminary data show decreased pancreatic vascularity in a placental insufficiency model of IUGR. Therefore, the long term goal of this proposal is to determie how the fetal nutrient supply reglulates pancreatic vascularity and angiogenesis. The overall hypothesis for this project is that pancreatic vascular endothelial growth factor A (VEGFA) and vascularity are positively regulated by the fetal glucose and amino acid supply and that underdevelopment of the pancreatic beta-cell in IUGR is due to decreased nutrient and insulin stimulated vascularity. We will use a unique combination of in vivo and in vitro studies to achieve these goals. This includes experimental manipulation of fetal nutrient supply in both normally growing and IUGR fetuses combined with analysis of pancreatic and islet vascularity, VEGFA and other angiogeneic growth factors, beta-cell function, mass, and replication, as well as isolation of fetal pancreatic islets and islet derived endothelial cells for functional analysis. In addition to the functional and developmental response of the fetal pancreas and beta-cell to nutrient manipulations, this project will provide important information on the overall response of the IUGR fetus to increased nutrient delivery which will have important implications for the field of fetal medicine and ultimately the development of fetal interventions for IUGR as well as the prevention of adult onset diabetes in previously growth restricted individuals. Finally, these projects will significantly increase our understanding of the regulation of beta-cell replication and mass and the cross-talk between endothelial cells and beta-cells, thereby providing important advances in the field of beta-cell biology.