Nutrient Coordination of Pancreatic Vasculature and Beta-Cells

描述（由申请人提供）：在发达国家，子宫内生长受限（IUGR）影响了4-8%的妊娠；最常见的病因是胎盘功能不全和胎儿营养供应减少。为了生存，胎儿会以最有效地利用有限能量供应的方式进行适应。胰腺细胞是这种适应的关键。β细胞分泌胰岛素，以营养调节的方式刺激胎儿生长。因此，胰腺β细胞是最重要的胎儿细胞类型之一，以匹配生长速度和营养供应。关于严重IUGR患者胰岛素分泌减少的机制的最佳证据是胰腺β细胞群的减少。实验证据表明，这些适应不能简单地通过向生长受限的胎儿提供更多的营养来克服。因此，任何治疗IUGR以提高胎儿生长速度的希望都必须结合增加胎儿营养输送和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，它们可能会导致先前生长受限的成年人患2型糖尿病的风险更高。新的证据显示胰腺血管系统和血管生成对于维持正常β细胞群和胰岛素分泌的重要性。与严重的人IUGR一致，我们的初步数据显示IUGR胎盘功能不全模型胰腺血管减少。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。本项目的总体假设是胰腺血管内皮生长因子A （VEGFA）和血管性受到胎儿葡萄糖和氨基酸供应的积极调节，IUGR中胰腺β细胞发育不足是由于营养和胰岛素刺激的血管性减少。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胎儿的营养供应进行实验操作，并结合胰腺和胰岛血管性、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细胞对营养调节的功能和发育反应外，该项目还将提供关于IUGR胎儿对增加营养输送的总体反应的重要信息，这将对胎儿医学领域产生重要影响，最终对IUGR胎儿干预的发展以及先前生长受限个体的成人发病糖尿病的预防具有重要意义。最后，这些项目将显著增加我们对β细胞复制和质量的调控以及内皮细胞与β细胞之间的串扰的理解，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. PUBLIC HEALTH RELEVANCE: This research is relevant to public health as it will demonstrate the mechanisms responsible for decreased fetal pancreatic islet vascularity, 2-cell mass, and insulin secretion in intrauterine growth restriction (IUGR). This will allow the development of prenatal therapies designed to improve fetal growth in IUGR and decrease the risk of these individuals developing type 2 diabetes mellitus as adults.