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

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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.