Nutrient coordination of pancreatic vasculature and B-cells

项目总结 宫内生长受限(IUGR)最常见的病因是胎盘功能不全和胎盘减少 胎儿营养供应。为了生存，胎儿的适应方式是促进最有效地利用 能源供应有限。胰腺β细胞在这种适应中起着关键作用。β细胞分泌胰岛素，这是 以一种营养调节的方式刺激胎儿生长。在IUGR中，胰岛素分泌受损。改编版 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，它们可能导致更高的2型糖尿病风险 以前的IUGR成人。新的证据显示了胰岛内皮细胞的重要性 (EC)用于成人正常胰岛素分泌。与人类IUGR一致，我们显示胰腺减少 胎儿宫内发育迟缓绵羊胎盘功能不全模型中的血管。我们还发现了受损的串音 在胰岛EC和β细胞之间。EC产生肝细胞生长因子和β-细胞产生 血管内皮生长因子A(VEGFA)降低。然而，重要的是，我们新奇的初步数据 表明增加IUGR胎羊的氨基酸供应可以恢复胎儿胰岛素的分泌，并增加 β-细胞质量和胰岛大小与胰岛血管的比例增加。因此，这一行动的长期目标是 建议是检验胎儿氨基酸供应减少是胎儿受损的原因的假设 胎儿宫内发育迟缓患者的胰腺血管、β细胞质量、胰岛大小和胰岛素分泌 抑制胰岛HGF和VEGFA的产生。在目标1中，我们将使用分离的胎羊胰岛和胰岛内皮细胞来 测定血管内皮生长因子刺激胰岛内皮细胞生长因子和肝细胞生长因子刺激β-细胞的能力 VEGFA制作。这将展示一种新的胰岛前馈HGF-VEGFA信号环路，它可以 协调胰岛生长和血管供应。此外，我们还将展示此信令可以在 当用适当的生长因子刺激时，IUGR胰岛。在目标2中，我们将测试假设 胰岛EC是一种新型的营养传感器，能在氨基酸增加时产生HGF，而EC 营养传感器对PI-IUGR中增加的氨基酸有响应。在目标3中，我们将检验假设 对PI-IUGR胎儿的长期氨基酸供应减少是胰岛HGF受损的主要原因。 VEGFA信号。在给胎儿输注各种氨基酸混合物后，我们将在体内测量胎儿胰岛素 分泌、胰岛大小和血管、β细胞团、以及分离的胰岛和胰岛EC信号和功能。这 研究结果表明，胎儿胰岛生长和血管供应的协调是 IUGR患者胰岛发育和胰岛素分泌受损。此外，我们将展示这个过程是 易于用氨基酸进行操作，以增加β细胞质量和胰岛素分泌。通过 我们的实验重点是β细胞对EC氨基酸的感知和信号传递，我们的实验将为 对IUGR后胰岛发育和预防糖尿病的新靶路径的洞察。

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.