Role of placental lactogens in regulating pancreatic beta-cell mass and function

胎盘催乳素在调节胰腺β细胞质量和功能中的作用

• 批准号: RGPIN-2015-04937
• 负责人: Huang, CarolTzuLing
• 金额: $ 1.75万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613266
• 关键词: Role; placental; lactogens; regulating; pancreatic

Pancreatic islets contain ß cells that synthesize insulin, the hormone responsible for maintaining normal blood glucose. We know that ß-cell mass and function is dynamic, and it can adapt to stresses such as pregnancy by increasing ß-cell mass and insulin secretion. We endeavor to study how ß-cell responds to its environment and mechanisms that regulate ß-cell mass and function. Previously, our studies have found that mice with a heterozygous deletion of prolactin receptor (Prlr), i.e. the Prlr+/- mice, had lower ß-cell number and secreted less insulin than wild type mice during pregnancy, suggesting that placental lactogens (PLs), which act on Prlr, have biological effects on ß cells. Since the Prlr deletion is in the whole body, not pancreas-specific, it is possible that the phenotype is secondary to overall diminished Prlr-mediated effects. To determine the mechanisms mediating ß-cell adaptation during pregnancy, I am seeking to discover the mechanism of how PLs regulate ß-cell mass and function. Our overall hypothesis is that PLs act directly on ß cells through its receptor (i.e. Prlr) to stimulate proliferation, insulin synthesis and secretion in adaptation to pregnancy. The long term objective of my research program is to understand the molecular mechanisms that control ß-cell growth and development. Our short term objectives are to study how PLs regulate ß-cell mass expansion and the molecular mechanisms involved. Aim 1. To determine the source of new ß cells in pregnancy. Using a transgenic mouse, we will tag ß cells that express a stem cell marker and then we will determine if these stem cells will develop into ß cells. Aim 2a. Characterize ß-cell mass and function in pancreas-specific Prlr-null mice. Using a transgenic mouse whereby Prlr will be deleted specifically from the pancreas after a drug is given, we will determine whether PLs regulate ß-cell proliferation by examining ß-cell mass and replication index. The impact of PLs on glucose homeostasis will be assessed by glucose and insulin tolerance tests. Aim 2b. Determine the molecular pathways regulated by Prlr in pancreatic ß cells. Many genes have been shown to regulate ß-cell biology during pregnancy. To determine which are Prlr-specific targets, we will compare their expression levels among the Prlr-null, pancreatic-specific Prlr-null and wild type mice. Aim 2c. To identify novel Prlr targets. A high throughput method will be used to screen for genes that are differentially expressed between pancreatic-specific Prlr-null and wild type mice. Genes that are identified as Prlr targets will be stratified based on putative function and further studied using pharmacological inhibitors or genetically-mediated gene deletion to determine their function. Results from this project will significantly advance our understanding of how ß-cell responds to its environment in adaptation to stresses.

胰岛含有合成胰岛素的胰岛细胞，胰岛素是负责维持正常血糖的激素。我们知道胰岛细胞的质量和功能是动态的，它可以通过增加胰岛细胞的质量和胰岛素分泌来适应怀孕等压力。我们奋进于研究胰岛细胞如何响应其环境和机制，调节胰岛细胞的质量和功能。以前，我们的研究发现，具有催乳素受体（Prlr）杂合缺失的小鼠，即Prlr+/-小鼠，在妊娠期间具有比野生型小鼠更低的β细胞数量和分泌更少的胰岛素，这表明作用于Prlr的胎盘催乳素（PL）对β细胞具有生物学效应。由于Prlr缺失是在整个身体中，而不是胰腺特异性的，因此该表型可能继发于总体减少的Prlr介导的作用。为了确定怀孕期间介导胰岛细胞适应的机制，我正在寻求发现PL如何调节胰岛细胞质量和功能的机制。我们的总体假设是，PL通过其受体（即Prlr）直接作用于胰岛细胞，以刺激增殖、胰岛素合成和分泌，从而适应妊娠。 我的研究计划的长期目标是了解控制胰岛细胞生长和发育的分子机制。我们的短期目标是研究磷脂酶如何调节胰岛细胞团的扩增及其分子机制。 目标1。确定妊娠期新生胰岛细胞的来源。使用转基因小鼠，我们将标记表达干细胞标志物的干细胞，然后我们将确定这些干细胞是否会发育成干细胞。 目标2a。表征胰腺特异性Prlr缺失小鼠中的胰岛细胞质量和功能。使用转基因小鼠，其中Prlr将在给予药物后从胰腺特异性地缺失，我们将通过检查胰腺细胞质量和复制指数来确定PL是否调节胰腺细胞增殖。PL对葡萄糖稳态的影响将通过葡萄糖和胰岛素耐量试验进行评估。 目标2b。确定Prlr在胰腺癌细胞中调节的分子途径。许多基因已被证明在怀孕期间调节胎盘细胞生物学。为了确定哪些是Prlr特异性靶标，我们将比较它们在Prlr缺失、胰腺特异性Prlr缺失和野生型小鼠中的表达水平。 目标2c。确定新的Prlr靶点。高通量方法将用于筛选胰腺特异性Prlr缺失和野生型小鼠之间差异表达的基因。将根据推定功能对被鉴定为Prlr靶点的基因进行分层，并使用药理学抑制剂或遗传介导的基因缺失进行进一步研究，以确定其功能。 该项目的结果将大大促进我们对细胞如何在适应压力时对其环境作出反应的理解。