The role of placental lactogens in the regulation of 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-2020-05247
• 负责人: Huang, CarolTzuLing
• 金额: $ 2.04万
• 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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740476
• 关键词: role; placental; lactogens; regulation; pancreatic

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.

胰岛含有合成胰岛素的ß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，通过增加胰岛素的产生来适应生理应激源，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代谢应激条件下调节ß-细胞质量、功能和存活的机制。我们发表的研究表明，催乳素受体（Prlr）在怀孕期间对母体ß-细胞适应至关重要，激活Prlr介导的信号传导以增加ß-细胞增殖和胰岛素合成是这种适应反应的一部分。然而，胰岛素合成增加会激活未折叠蛋白反应（UPR），如果未解决，将导致内质网（ER）应激和细胞凋亡。一项基于发现的实验发现Lrrc55是妊娠期间ß细胞中的一种新的促生存因子。Lrrc55是一种被认为具有大电导、Ca2+激活的K+通道的辅助蛋白。妊娠期间胰岛中Lrrc55的表达上调，也可通过游离脂肪酸（FFA）的细胞毒性浓度、肥胖和内质网应激的化学诱导而上调。过表达实验发现，它可能通过维持ER Ca2+储存来阻止ffa介导的持续UPR激活和ß-细胞凋亡。我们假设Lrrc55调节ß细胞中ER Ca2+通道的活性。Prlr的普遍表达提出了Prlr在ß细胞上具有非细胞自主作用的可能性。为了解决这个问题，我们培育了一只具有可诱导的、ß-细胞特异性Prlr缺失的转基因小鼠。比较全局和ß-细胞特异性Prlr-null小鼠发现了保护ß细胞免受凋亡的基因表达的重要差异，支持了Prlr在调节ß-细胞存活中具有非细胞自主作用的假设。prlr介导的ß-细胞适应妊娠的作用可能适用于胰岛素抵抗的其他生理状况，即营养过剩和衰老。支持这一点，我们发现怀孕杂合Prlr+/-小鼠的胰岛更容易受到ffa诱导的细胞凋亡，Prlr-/-小鼠的胰岛表达更高水平的ß-细胞老化标志物。这些观察结果表明，Prlr可能在怀孕之外具有广泛的有益作用。我们的目标是了解Prlr如何调节ß-细胞对代谢应激源的适应。我们将研究1)新的Prlr靶点的功能和信号机制，特别是Lrrc55的作用，2)Prlr的非细胞自主作用，以及3)Prlr在保护ß细胞免受妊娠、营养过剩和衰老带来的代谢应激中的作用。我们的课程涵盖生物化学，细胞和分子生物学，以及整个生物体生理学，为高素质人才提供了良好的培训机会。