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：
7639887
负责人：
Paul Joseph Rozance
金额：
$ 13.23万
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 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7639887
关键词：
Acute Adult Affect Animal Model Beta Cell Birth Cell physiology Cells Chronic Defect Developed Countries Developing 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 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 public health relevance response therapy design

项目摘要

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 (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 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 p-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 p-cell insulin secretion. Additionally, if these adaptations which limit the fetal p-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. The long-term goal of this project is to determine the responsible mechanisms for limiting the 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-cell to endothelial cell signaling for maintenance of the normal p-cell population and insulin secretion. Therefore, this proposal will specifically examine decreased p-cell to endothelial cell signaling as the cause of decreased p-cell mass and insulin secretion in a fetal sheep model of placental insufficiency 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 endothelial cells is decreased. We will then demonstrate the consequences of decreased pancreatic islet endothelial cell function by measuring pancreatic islet vascularity and angiogenesis in IUGR fetuses. Finally, we will determine if chronically increasing insulin concentrations in the IUGR fetus can improve pancreatic islet vascularity, angiogenesis, and P-cell mass. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：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，胎儿以促进最有效地利用有限能量供应的方式进行适应。胰腺（3-细胞）是这种适应的关键。p-细胞分泌胰岛素，以营养调节的方式刺激胎儿生长。因此，胰腺（3-细胞）是匹配生长速率的最重要的胎儿细胞类型之一关于严重IUGR中胰岛素分泌减少的机制的最佳证据是胰腺p细胞数量的减少，因此不能简单地通过向生长受限的胎儿提供更多的营养来克服这些适应。 , 任何希望治疗 IUGR 来提高胎儿生长速度必须结合增加胎儿营养输送和 P 细胞胰岛素分泌的策略。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到成年期，它们可能会导致更高的风险。该项目的长期目标是确定限制 IUGR 中胎儿 P 细胞群和胰岛素分泌的机制，最终开发干预措施来扭转这些适应和变化。允许治疗IUGR 和 2 型糖尿病的预防。新的证据不断出现，表明 p 细胞对内皮细胞信号传导对于维持正常 p 细胞群和胰岛素分泌的重要性。因此，本提案将专门检查 p 细胞与内皮细胞信号传导的减少，作为胎盘功能不全和 IUGR 胎羊模型中 p 细胞质量和胰岛素分泌减少的原因。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，并表明 IUGR 胰岛内皮细胞的反应降低。然后，我们将通过测量 IUGR 胎儿的胰岛血管分布和血管生成来证明胰岛内皮细胞功能下降的后果。最后，我们将确定长期增加 IUGR 胎儿的胰岛素浓度是否可以改善胰岛血管分布、血管生成和 P 细胞质量。公共健康相关性：这项研究与公共健康相关，因为它将证明宫内生长受限 (IUGR) 中胎儿 p 细胞质量和胰岛素分泌减少的机制。这将有助于开发旨在改善 IUGR 胎儿生长并降低这些个体成年后患 2 型糖尿病的风险的产前治疗。