Nutrient coordination of pancreatic vasculature and B-cells

项目摘要 胎儿宫内生长受限（IUGR）最常见的病因是胎盘功能不全， 胎儿营养供应为了生存，胎儿适应的方式，促进最有效地利用一个 有限的能源供应。胰腺β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。在IUGR胰岛素分泌受损。的适应化修改 导致胰岛素分泌减少的原因包括β细胞质量降低和胰岛发育受损。如果 这些适应持续到成年期，它们可能导致2型糖尿病的高风险， 以前IUGR成人。新的证据显示了胰岛内皮细胞的重要性 (EC)正常的成人胰岛素分泌。与人类IUGR一致，我们发现胰腺癌的发生率降低， IUGR羊胎盘功能不全模型中的血管分布。我们还发现了受损的串扰 胰岛EC与β细胞之间的关系。EC产生肝细胞生长因子（HGF），β细胞产生 血管内皮生长因子A（VEGFA）降低。重要的是，我们的新的初步数据 显示增加IUGR胎羊中氨基酸供应恢复了胎儿胰岛素分泌， β细胞质量和胰岛大小，胰岛血管分布成比例增加。因此，这一长期目标 一项建议是检验胎儿氨基酸供应减少是胎儿发育受损的原因这一假设。 IUGR中胰腺血管分布、β细胞质量、胰岛大小和胰岛素分泌，这是由 抑制胰岛HGF和VEGFA产生。在目标1中，我们将使用分离的胎羊胰岛和胰岛EC， 测定VEGFA刺激胰岛EC HGF产生的能力和HGF刺激β细胞的能力， VEGFA生产。这将证明一种新的胰岛前馈HGF-VEGFA信号环， 协调胰岛生长和血管供应。此外，我们将表明，这种信号可以增加， 当用适当的生长因子刺激时，IUGR胰岛。在目标2中，我们将检验以下假设： 胰岛EC是一种新型的营养传感器，其响应于增加的氨基酸而产生HGF，并且EC 营养传感器对PI-IUGR中增加的氨基酸有反应。在目标3中，我们将检验以下假设： PI-IUGR胎儿的氨基酸供应的慢性减少是胰岛HGF受损的主要原因。 VEGFA信号传导。在胎儿输注各种氨基酸混合物后，我们将测量体内胎儿胰岛素 分泌、胰岛大小和血管分布、β细胞质量以及分离的胰岛和胰岛EC信号传导和功能。这 该提案将表明，胎儿胰岛生长和血管供应的协调是糖尿病发病机制的关键。 IUGR中胰岛发育和胰岛素分泌受损。此外，我们将证明这个过程是 这是一种易于用氨基酸以增加β细胞质量和胰岛素分泌的方式进行操作的方法。通过 我们的实验将重点放在EC氨基酸传感和β细胞的信号传导上， 深入了解胰岛发育和预防IUGR后糖尿病的新靶向途径。

PROJECT SUMMARY The most common etiology of intrauterine growth restriction (IUGR) is 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 β-cells are key in this adaptation. The β-cell secretes insulin, which stimulates fetal growth, in a nutrient regulated fashion. In IUGR insulin secretion is impaired. The adaptations resulting in decreased insulin secretion include lower β-cell mass and impaired pancreatic islet development. If these adaptations persist into adulthood they can contribute to the higher risk of type 2 diabetes mellitus in previously IUGR adults. New evidence is emerging which shows the importance of the islet endothelial cell (EC) for normal adult insulin secretion. Consistent with human IUGR, we show decreased pancreatic vascularity in a sheep placental insufficiency model of IUGR. We also have identified impaired cross talk between the islet EC and β-cell. Both EC produced hepatocyte growth factor (HGF) and β-cell produced vascular endothelial growth factor A (VEGFA) are decreased. Importantly, though, our novel preliminary data show that increasing the amino acid supply in IUGR fetal sheep restores fetal insulin secretion and increases β-cell mass and islet size with a proportional increase in islet vascularity. Therefore, the long term goal of this proposal is to test the hypothesis that reduced fetal amino acid supply is responsible for impaired fetal pancreatic vascularity, β-cell mass, islet size, and insulin secretion in IUGR and that this is mediated by inhibition of islet HGF and VEGFA production. In Aim 1 we will use isolated fetal sheep islets and islet ECs to determine the capacity for VEGFA to stimulate islet EC HGF production and for HGF to stimulate β-cell VEGFA production. This will demonstrate a novel islet feed forward HGF-VEGFA signaling loop which can coordinate islet growth with vascular supply. Furthermore, we will show that this signaling can be increased in IUGR islets when stimulated with the appropriate growth factors. In Aim 2 we will test the hypothesis that the islet EC is a novel nutrient sensor producing HGF in response to increased amino acids, and that the EC nutrient sensor is responsive to increased amino acids in PI-IUGR. In aim 3 we will test the hypothesis that chronically decreased amino acid supply to the PI-IUGR fetus is primarily responsible for impaired islet HGF- VEGFA signaling. Following fetal infusions of various amino acid mixtures we will measure in vivo fetal insulin secretion, islet size and vascularity, β-cell mass, and isolated islet and islet EC signaling and function. This proposal will show that the coordination of fetal islet growth and vascular supply is key in the pathogenesis of impaired islet development and insulin secretion in IUGR. Furthermore, we will show that this process is amenable to manipulation with amino acids in a way that will increase β-cell mass and insulin secretion. By focusing on EC amino acid sensing and signaling with the β-cell, our experiments will provide mechanistic insights into islet development and new target pathways for the prevention of diabetes following IUGR.