Nutrient Coordination of Pancreatic Vasculature and Beta-Cells

胰腺脉管系统和β细胞的营养协调

• 批准号: 8513983
• 负责人: Paul Joseph Rozance
• 金额: $ 47.58万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513983
• 关键词: Address; Adult; Affect; Amino Acids; Beta Cell; Biological Preservation; Biology; Cell physiology; Cells; Cellular biology; Complex; Data; Defect; Developed Countries; Development; Diabetes Mellitus; Endothelial Cells; Energy Supply; Etiology; Feeding Patterns; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetus; Functional disorder; Glucose; Goals; Growth; Growth Factor; Hormonal; Human; In Vitro; Individual; Infant; Infusion procedures; Insulin; Intervention; Islets of Langerhans; Knowledge; Lead; Link; Maintenance; Mediating; Modeling; Natural regeneration; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional status; Pancreas; Patients; Placental Insufficiency; Population; Pregnancy; Prevention; Public Health; Regulation; Relative (related person); Research; Risk; Sheep; Signal Transduction; Structure of beta Cell of islet; Time; Transplantation; Vascular Endothelial Growth Factor A; angiogenesis; cell type; fetal; fetal medicine; fetus cell; high risk; improved; in vivo; insulin secretion; islet; novel strategies; nutrient metabolism; pancreatic islet function; postnatal; prenatal therapy; prevent; research study; response; therapy design

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.

描述（由申请人提供）：宫内生长限制（IUGR）影响发达国家所有怀孕的4-8％；最常见的病因是胎盘不足和胎儿营养供应减少。为了生存，胎儿以促进有限能源供应的最有效利用的方式适应。胰腺β细胞是此适应性的关键。 β细胞分泌的胰岛素以营养调节的方式刺激胎儿生长。因此，胰腺β细胞是将生长速率与营养供应相匹配的最重要的胎儿细胞类型之一。关于严重人IUGR胰岛素分泌降低机制的最佳证据是胰腺β细胞种群的降低。实验证据表明，这些适应不能仅仅通过为限制胎儿提供增加的营养来克服。因此，任何治疗IUGR提高胎儿生长率的希望都必须结合增加胎儿营养递送和β细胞胰岛素分泌的策略。此外，如果这些适应限制了胎儿β细胞种群和胰岛素的分泌持续到成年期，则可以在先前成长的成年人中有助于较高的2型糖尿病风险。新的证据正在出现，这表明胰腺脉管系统和血管生成对维持正常β细胞种群和胰岛素分泌的重要性。与严重的人IUGR一致，我们的初步数据表明，在IUGR的胎盘不足模型中，胰腺血管降低。因此，该提案的长期目标是确定胎儿营养供应如何重新延长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）和血管性受胎儿葡萄糖和氨基酸供应的积极调节，并且IUGR中胰腺β-细胞的不足是由于IUGR中的不足而造成的，这是由于营养和胰岛素刺激的降低而导致的。我们将使用体内和体外研究的独特组合来实现这些目标。这包括在正常生长和IUGR胎儿中对胎儿营养供应的实验性操纵，以及分析胰腺和胰岛血管，VEGFA和其他血管生成性生长因子，β细胞功能，质量和复制，以及胎儿胰岛和胰岛胰岛胰岛和胰岛脱发分析的隔离。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胎儿对增加营养递送的整体反应的重要信息，这将对胎儿医学领域以及最终对IUGR胎儿干预的发展具有重要意义，以及对IGR的胎儿干预以及对成人糖尿病患者的预测。最后，这些项目将大大提高我们对β细胞复制和质量的调节以及内皮细胞和β细胞之间的串扰的理解，从而在β细胞生物学领域提供了重要的进步。