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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717577
• 关键词: role; placental; lactogens; regulation; pancreatic

Pancreatic islets contain cells that synthesize insulin, the main hormone responsible for glucose utilization. Pancreatic -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 -cell mass, function, and survival under normal and metabolically stressed conditions. Our published work showed that the prolactin receptor (Prlr) is vital for maternal -cell adaptation during pregnancy, and that activation of Prlr-mediated signaling to increase -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 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 -cell apoptosis by maintaining ER Ca2+ store. We hypothesize that Lrrc55 regulates the activity of ER Ca2+ channels in cells. The ubiquitous expression of Prlr raise the possibility that Prlr has a non-cell autonomous role on cells. To address this, we generated a transgenic mouse with an inducible, -cell-specific Prlr deletion. Comparing global vs. -cell specific Prlr-null mice identified important differences in the expression of genes that protect cells against apoptosis, supporting the hypothesis that Prlr has a non-cell autonomous role in the regulation of -cell survival. The Prlr-mediated effects on -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 -cell aging marker. These observations suggest that Prlr may have a broad beneficial role beyond pregnancy. Our objective is to understand how Prlr regulates -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 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源，如妊娠的胰岛素抵抗、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）是至关重要的母体细胞在怀孕期间的适应，并激活Prlr介导的信号，以增加细胞增殖和胰岛素合成是这种适应性反应的一部分。然而，增加的胰岛素合成激活未折叠蛋白反应（UPR），如果未解决，则导致内质网（ER）应激和细胞凋亡。 一项基于发现的实验将Lrrc 55鉴定为妊娠期间细胞中的一种新的促存活因子。Lrrc 55是一种推定的大电导、Ca 2+激活的K+通道的辅助蛋白。Lrrc 55表达在妊娠期间的胰岛中上调，以及通过游离脂肪酸（FFA）的细胞毒性浓度、肥胖和通过ER应激的化学诱导上调。过表达实验发现，它可能阻止FFA介导的激活持续UPR和细胞凋亡维持ER Ca 2+库。我们假设Lrrc 55调节细胞中ER Ca 2+通道的活性。 Prlr的普遍表达提高了Prlr对细胞具有非细胞自主作用的可能性。为了解决这个问题，我们产生了一个转基因小鼠诱导，细胞特异性Prlr缺失。比较全球与细胞特异性Prlr-空小鼠确定了重要的差异，保护细胞凋亡的基因的表达，支持的假设，Prlr有一个非细胞自主的作用，在调节细胞的生存。PRLR介导的对细胞适应妊娠的影响可能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，从怀孕的杂合子Prlr+/-小鼠的胰岛更容易受到FFA诱导的细胞凋亡和从Prlr-/-小鼠的胰岛表达更高水平的α-细胞老化标志物。这些观察结果表明，PRLR可能有一个广泛的有益作用超越怀孕。 我们的目标是了解Prlr如何调节细胞对代谢应激的适应。我们将研究1）新型Prlr靶点的功能和信号传导机制，特别是Lrrc 55的作用，2）Prlr的非细胞自主作用，3）Prlr在保护细胞免受妊娠，营养过剩和衰老引起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，为高素质的人才提供良好的培训机会。