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

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如何调控？细胞质量扩张及其相关的分子机制。 目的1.确定孕期新细胞的来源。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。

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.