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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=679968
• 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？细胞，胰岛素是一种负责维持正常血糖的激素。我们知道，肌细胞的质量和功能是动态的，它可以通过增加肌细胞质量和胰岛素分泌来适应压力，比如怀孕。我们致力于研究？细胞如何对其环境作出反应，以及调节？细胞质量和功能的机制。此前，我们的研究发现，PRLR杂合性缺失的小鼠，即PrLR+/-小鼠，在妊娠期比野生型小鼠有更少的？细胞数量和更少的胰岛素分泌，这表明作用于PrLR的胎盘催乳素(Pls)对？细胞有生物学效应。由于PrlR的缺失发生在全身，而不是胰腺特有的，因此可能该表型是次要的，而不是整个Prlr介导的效应减弱。为了确定在怀孕期间调节？细胞适应的机制，我试图发现PERS如何调节？细胞质量和功能的机制。我们的总体假设是，在适应妊娠的过程中，PERS通过其受体(即Prlr)直接作用于？细胞，刺激其增殖、胰岛素合成和分泌。*我的研究计划的长期目标是了解控制？细胞生长和发育的分子机制。我们的短期目标是研究PERS如何调节？细胞质量的扩大及其涉及的分子机制。*目的1.确定妊娠中新的？细胞的来源。使用转基因小鼠，我们将标记表达干细胞标记的？细胞，然后我们将确定这些干细胞是否会发育成？细胞。*目标2a。鉴定胰腺特异性Prlr基因缺失小鼠的？细胞质量和功能。使用转基因小鼠，在给药后Prlr将从胰腺中特定地删除，我们将通过检查？细胞质量和复制指数来确定pls是否调节？细胞增殖。PLS对血糖稳态的影响将通过葡萄糖和胰岛素耐量试验来评估。*目标2b。确定PrlR在胰腺细胞中调控的分子通路。许多基因已经被证明在怀孕期间调节？细胞生物学。为了确定哪些是Prlr特异性靶点，我们将比较Prlr缺失、胰腺特异性Prlr缺失和野生型小鼠中它们的表达水平。*目标2c.以确定新的Prlr目标。一种高通量的方法将用于筛选胰腺特异性Prlr缺失小鼠和野生型小鼠之间差异表达的基因。被确认为Prlr靶标的基因将根据假定的功能进行分层，并使用药物抑制剂或基因介导的基因缺失进行进一步研究，以确定其功能。*这一项目的结果将极大地促进我们对ç-cell如何在适应压力的过程中对环境做出反应的理解。**