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.

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，胎儿适应促进有限能源供应的最有效利用的方法。适应。 P细胞分泌的胰岛素以营养调节的方式刺激胎儿生长。所以，胰腺（3细胞是与营养供应相匹配的生长速率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减少胰腺P细胞种群。表明无法克服这些适应仅通过为限制胎儿提供养分。因此，任何希望对待IUGR的希望提高胎儿的生长速率将必须结合增加胎儿营养递送和P-胞糖蛋白的策略分泌。此外，如果这些适应限制胎儿P细胞种群和胰岛素分泌的改编成年后，他们可以在先前生长限制的2型糖尿病风险中造成更高的风险成年人。该项目的长期目标是确定限制胎儿P细胞的负责任机制 IUGR中的人口和胰岛素分泌，目的是最终开发干预措施以扭转这些干预措施适应并允许治疗IUGR和预防2型糖尿病。新证据正在出现显示了p-cellto内皮细胞信号对维持正常P细胞种群和的重要性胰岛素分泌。因此，该建议将专门检查降低的P细胞至内皮细胞的降低作为胎盘绵羊模型的dec骨肿块和胰岛素的原因 iugr。我们将使用体外测定法测量急性P细胞和胰岛素刺激的内皮细胞功能，以及表明IUGR胰岛内皮细胞的响应减少了。然后，我们将证明通过测量胰岛的胰岛内皮功能降低的后果和IUGR胎儿的血管生成。最后，我们将确定是否长期促成胰岛素浓度 IUGR胎儿可以改善胰岛血管，血管生成和P细胞质量。相关性（请参阅说明）：这项研究与公共卫生有关，因为它将证明负责减少的机制宫内生长限制（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胎儿生长的产前疗法并降低了这些疗法的风险成年后，患有2型糖尿病的人。