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Pancreatic beta-cell endothelial cell function and signaling in intrauterine grow

子宫内生长中的胰腺β细胞内皮细胞功能和信号传导

基本信息

批准号：
8521330
负责人：
Paul Joseph Rozance
金额：
$ 9.72万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8521330
关键词：
Acute Adult Affect Animal Model Beta Cell Birth Cell physiology Cells Chronic Defect Developed Countries Development Endothelial Cells Energy Supply Environment Epidemiology Etiology Feedback Fetal Growth Fetal Growth Retardation Fetus Glucose Goals Growth Human Hypoglycemia Hypoxia In Vitro Individual Infusion procedures Instruction Insulin Intervention Islets of Langerhans Maintenance Measures Modeling Non-Insulin-Dependent Diabetes Mellitus Nutrient Oxygen Pancreas Pathway interactions Placental Insufficiency Population Pregnancy Prevention Principal Investigator Public Health Regulation Research Risk Sheep Signal Transduction Structure Structure of beta Cell of islet Time angiogenesis animal data blood glucose regulation cell type fetal fetus cell glucose uptake high risk improved in vitro Assay in vivo insulin secretion intercellular communication islet prenatal therapy response therapy design

项目摘要

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 (3-cells are key in this adaptation. The p-cell secretes insulin, which stimulates fetal growth, in a nutrient regulated fashion. Therefore, the pancreatic (3-cell is one of the most important fetal cell types for matchinggrowth rates to nutrient supply. The best evidence regarding the mechanism of decreased insulin secretion in severe human IUGR is a decrease in the pancreatic p-cell population.Experimentalevidence suggests that these adaptations cannot be overcome simply by providingincreased 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 p-cellinsulin secretion. Additionally, ifthese adaptations which limitthe fetal p-cell populationand insulin secretion persist into adulthood they can contribute to the higher risk of type 2 diabetes mellitus in previously growth restricted adults. The longterm goal of this project is to determine the responsible mechanisms for limitingthe fetal p-cell population and insulin secretion in IUGR with the aim of eventually developing interventions to reverse these adaptations and allow for treatment of IUGR and prevention of type 2 diabetes. New evidence is emerging which shows the importance of p-cellto endothelial cell signalingfor maintenance of the normal p-cell populationand insulin secretion. Therefore, this proposal will specifically examine decreased p-cell to endothelial cellsignaling as the cause of decresaed p-cell mass and insulinsecretion in a fetal sheep model of placental insufficincy and IUGR. We will use in vitro assays to measure acute p-cell and insulin stimulated endothelial cell function and show that the response of IUGR pancreatic islet endothelialcells is decreased. We will then demonstrate the consequences of decreased pancreatic islet endothelialcell function by measuringpancreatic isletvascularity and angiogenesis in IUGR fetuses. Finally, we will determine if chronicallyincreasing insulin concentrations in the IUGR fetus can improve pancreatic islet vascularity,angiogenesis, and P-cell mass. RELEVANCE (See instructions): This research is relevant to public health as it will demonstrate the mechanisms responsible for decreased fetal p-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.

在发达国家，宫内生长受限 (IUGR) 影响着 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，胎儿必须适应促进最有效地利用有限能源供应的方法。胰腺（3 细胞是其中的关键适应。 p 细胞分泌胰岛素，以营养调节的方式刺激胎儿生长。所以，胰腺（3 细胞）是最重要的胎儿细胞类型之一，用于使生长速率与营养供应相匹配。关于严重人类 IUGR 胰岛素分泌减少机制的最佳证据是胰腺 p 细胞群。实验证据表明这些适应无法克服只需为生长受限的胎儿提供更多的营养即可。因此，治疗 IUGR 的任何希望提高胎儿生长速度必须结合增加胎儿营养输送和 p-细胞胰岛素的策略分泌。此外，如果这些限制胎儿 P 细胞数量和胰岛素分泌的适应持续存在成年后，他们可能会导致先前生长受限的人患 2 型糖尿病的风险更高成年人。该项目的长期目标是确定限制胎儿 p 细胞的机制 IUGR 中的人口和胰岛素分泌，目的是最终制定干预措施来扭转这些适应并允许治疗 IUGR 和预防 2 型糖尿病。新的证据正在出现显示 p 细胞与内皮细胞信号转导对于维持正常 p 细胞群的重要性胰岛素分泌。因此，该提案将专门检查 p 细胞至内皮细胞信号传导的减少作为胎盘功能不全胎羊模型中 P 细胞质量和胰岛素分泌减少的原因， IUGR。我们将使用体外测定来测量急性 p 细胞和胰岛素刺激的内皮细胞功能，并显示IUGR胰岛内皮细胞的反应降低。然后我们将演示通过测量胰岛血管分布来观察胰岛内皮细胞功能下降的后果和 IUGR 胎儿的血管生成。最后，我们将确定是否长期增加胰岛素浓度 IUGR胎儿可以改善胰岛血管分布、血管生成和P细胞质量。相关性（参见说明）：这项研究与公共卫生相关，因为它将证明导致减少的机制宫内生长受限 (IUGR) 中的胎儿 P 细胞质量和胰岛素分泌。这将允许开发旨在改善 IUGR 胎儿生长并降低这些风险的产前治疗成年后患有 2 型糖尿病的个体。