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

描述(由申请人提供)：在发达国家，宫内生长受限(IUGR)影响所有妊娠的4-8%；最常见的原因是胎盘功能不全和胎儿营养供应减少。为了生存，胎儿以促进有限能量供应的最有效利用的方式进行适应。胰腺(3-细胞是这种适应的关键。P细胞以一种营养调节的方式分泌胰岛素，刺激胎儿生长。因此，胰腺(3-细胞)是使生长速度与营养供应相匹配的最重要的胎儿细胞类型之一。关于严重的人类IUGR患者胰岛素分泌减少的机制，最好的证据是胰腺p细胞数量的减少。实验证据表明，这些适应不是简单地通过向生长受限的胎儿提供更多的营养来克服的。因此，治疗IUGR以提高胎儿生长率的任何希望都必须结合增加胎儿营养供应和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，它们可能会导致以前生长受限的成年人患2型糖尿病的风险更高。该项目的长期目标是确定在IUGR中限制胎儿p细胞数量和胰岛素分泌的负责机制，目的是最终开发出逆转这些适应的干预措施，并允许治疗IUGR和预防2型糖尿病。新的证据表明，p-细胞对内皮细胞信号转导对于维持正常p-细胞群和胰岛素分泌的重要性。因此，在胎盘功能不全和宫内发育迟缓的胎羊模型中，该方案将专门研究p-细胞-内皮细胞信号转导减少作为p-细胞质量和胰岛素分泌减少的原因。我们将使用体外实验检测急性胰岛β细胞和胰岛素刺激的内皮细胞功能，显示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、血管生成和P细胞质量。 公共卫生相关性：这项研究与公共健康相关，因为它将证明胎儿p细胞质量和胰岛素分泌减少在胎儿宫内生长受限(IUGR)中的作用机制。这将允许开发旨在改善IUGR胎儿生长发育的产前治疗方法，并降低这些人成年后患2型糖尿病的风险。

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.