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）：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（3个细胞是这种适应的关键。P细胞分泌胰岛素，以营养受调节的方式刺激胎儿生长，胰岛细胞（3细胞是与营养供应相匹配的最重要的胎儿细胞类型之一，是对养分的最佳证据的最佳证据。关于胰岛素的最佳证据。提出这些适应性不能仅通过为限制的胎儿提供增加的营养来克服，因此，任何对IUGR改善胎儿生长速度的希望都必须结合使用胎儿营养递送和P细胞胰岛素分泌的策略。以前，成年人的长期限制。新的证据正在出现，这表明了P细胞对内皮细胞信号的重要性，对维持正常P细胞种群和胰岛素分泌的重要性。因此，该建议将专门研究降低的P细胞对内皮细胞信号传导的减少，是胎盘绵羊不足和IUGR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法测量急性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减少了。然后，我们将通过测量IUGR胎儿的胰岛血管和血管生成来证明胰岛内皮细胞功能减少的后果。最后，我们将确定IUGR胎儿中长期增加的胰岛素浓度是否可以改善胰岛血管性，血管生成和P细胞质量。公共卫生相关性：这项研究与公共卫生有关，因为它将证明导致宫内生长限制（IUGR）中胎儿P细胞质量和胰岛素分泌减少的机制。这将允许开发旨在改善IUGR胎儿生长的产前疗法，并降低这些人成年后发展2型糖尿病的风险。