The role of placental lactogens in the regulation of pancreatic beta-cell mass and function

胰岛含有合成胰岛素的？细胞，胰岛素是负责葡萄糖利用的主要激素。胰腺细胞的质量和功能是动态的，并通过增加胰岛素的产生来适应生理应激因素，如妊娠胰岛素抵抗、营养过剩和衰老。我的NSERC项目的长期目标是了解在正常和新陈代谢应激条件下调节？细胞质量、功能和存活的机制。我们已发表的工作表明，催乳素受体(Prlr)对孕期母体？细胞适应至关重要，而Prlr介导的促进？细胞增殖和胰岛素合成的信号激活是这种适应性反应的一部分。然而，胰岛素合成增加会激活未折叠蛋白反应(UPR)，如果不解决这一问题，就会导致内质网(ER)应激和细胞凋亡。一项以发现为基础的实验发现，Lrrc55是怀孕期间？细胞中的一种新的促生存因子。Lrrc55是一种可能的大电导、钙激活K+通道辅助蛋白。在怀孕期间，Lrrc55在胰岛中的表达上调，以及细胞毒性浓度的游离脂肪酸(FFA)，肥胖和化学诱导的内质网应激。过表达实验发现，它可能通过维持内质网钙存储来阻止FFA介导的持续UPR激活和ç-细胞凋亡。我们假设Lrrc55调节？细胞内内质网钙通道的活动。PrlR的无处不在的表达增加了PrlR在？细胞上具有非细胞自治作用的可能性。为了解决这个问题，我们培育了一只转基因小鼠，该小鼠具有可诱导的、？细胞特异性的PrlR缺失。通过比较全局Prlr基因缺失小鼠和矿化细胞特异性Prlr基因缺失小鼠，发现了保护矿化细胞免于凋亡的基因表达的重要差异，支持了Prlr在调节矿化细胞存活方面具有非细胞自主作用的假说。Prlr介导的细胞对妊娠适应性的影响可能也适用于胰岛素抵抗的其他生理条件，即营养过剩和衰老。支持这一点，我们发现怀孕的杂合子Prlr+/-小鼠的胰岛更容易受到FFA诱导的凋亡，并且来自Prlr-/-小鼠的胰岛表达更高水平的？细胞衰老标记物。这些观察结果表明，Prlr可能在怀孕后具有广泛的有益作用。我们的目标是了解Prlr如何调节？细胞对新陈代谢应激源的适应。我们将研究1)新的PrlR靶标的功能和信号机制，特别是Lrrc55的作用，2)PrlR的非细胞自主作用，以及3)PrlR在保护？细胞免受怀孕、营养过剩和衰老施加的代谢压力中的作用。我们的课程涵盖生物化学、细胞和分子生物学以及整体生理学，为高素质人才提供了极好的培训机会。

Pancreatic islets contain ß cells that synthesize insulin, the main hormone responsible for glucose utilization. Pancreatic ß-cell mass and function are dynamic and adapts to physiological stressors such as insulin resistance of pregnancy, nutrient excess, and aging by increasing insulin production. The long-term goal of my NSERC program is to understand the mechanisms that regulate ß-cell mass, function, and survival under normal and metabolically stressed conditions. Our published work showed that the prolactin receptor (Prlr) is vital for maternal ß-cell adaptation during pregnancy, and that activation of Prlr-mediated signaling to increase ß-cell proliferation and insulin synthesis is part of this adaptive response. Increased insulin synthesis, however, activates the unfolded protein response (UPR), which if unresolved, leads to endoplasmic reticulum (ER) stress and apoptosis. A discovery-based experiment identified Lrrc55 as a novel pro-survival factor in ß cells during pregnancy. Lrrc55 is a putative auxiliary protein of large conductance, Ca2+-activated K+ channels. Lrrc55 expression is upregulated in islets during pregnancy, as well by cytotoxic concentration of free fatty acids (FFA), in obesity, and by chemical induction of ER stress. Overexpression experiments found that it likely prevented FFA-mediated activation of sustained UPR and ß-cell apoptosis by maintaining ER Ca2+ store. We hypothesize that Lrrc55 regulates the activity of ER Ca2+ channels in ß cells. The ubiquitous expression of Prlr raise the possibility that Prlr has a non-cell autonomous role on ß cells. To address this, we generated a transgenic mouse with an inducible, ß-cell-specific Prlr deletion. Comparing global vs. ß-cell specific Prlr-null mice identified important differences in the expression of genes that protect ß cells against apoptosis, supporting the hypothesis that Prlr has a non-cell autonomous role in the regulation of ß-cell survival. The Prlr-mediated effects on ß-cell adaptation to pregnancy are likely to be applicable in other physiological conditions of insulin resistance, namely nutrient excess and aging. Supporting this, we found that islets from pregnant heterozygous Prlr+/- mice were more susceptible to FFA-induced apoptosis and islets from Prlr-/- mice expressed a higher level of a ß-cell aging marker. These observations suggest that Prlr may have a broad beneficial role beyond pregnancy. Our objective is to understand how Prlr regulates ß-cell adaptation to metabolic stressors. We will investigate 1) the function and signaling mechanism of novel Prlr targets, specifically the actions of Lrrc55, 2) the non-cell autonomous role of Prlr, and 3) the role of Prlr in protecting ß cells against metabolic stresses imposed by pregnancy, nutrient excess, and aging. Our program spans biochemistry, cellular and molecular biology, and whole organism physiology, providing excellent training opportunities for highly qualified personnel.