Deciphering the link between stress and regeneration in pancreatic beta cells

破译胰腺β细胞压力与再生之间的联系

• 批准号: 406423201
• 负责人: Professor Michele Solimena
• 金额: --
• 依托单位: Institut Pasteur de Lille
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/406423201?language=en
• 关键词: Deciphering; link; between; stress; regeneration

The survival and normal function of cells depend on ubiquitously expressed signalling pathways that protect against proteotoxic and genotoxic stress as well as stress due to infection or inflammation. Among these pathways, the unfolded protein response (UPR) protecting against dangerous protein overload in the endoplasmic reticulum is especially important for highly active secretory cells. Pancreatic beta cells cope with variable metabolic insulin demand by constitutive and inducible engagement of the UPR. Recent results suggest that the UPR not only increases insulin folding and secretion capacity but can also induces beta cell proliferation through an unknown mechanism. We have found that deletion of a protease of beta cells upregulates the UPR and induces a strong proliferative response in murine beta cells. At the same time, non-obese diabetic mice deficient for such protease are protected from autoimmune diabetes, and their beta cells protected from T cell killing. The objective of this study will be to determine the underlying mechanism and signalling pathways and potentially identify targets for pharmacological modulation of stress responses. The project brings together highly complementary teams contributing i) a substantial set of preliminary data on mice and beta cells lacking such protease, ii) strong expertise on beta cell physiology and insulin processing, and iii) expertise in robotized small molecule screening approaches. In this project we will study the effect of deleting such protease on beta cell physiology, monitoring specifically insulin synthesis, processing and turnover using cell biological approaches. The objective of a second workpackage will be to analyse how the deficiency for this protease affects the innate and adaptive immune response to beta cells and specifically protects them from killing. Moreover, we will examine how absence of this protease triggers the UPR and how this is linked to beta cell regeneration, using cell biological, genomics and proteomics approaches. This will be studied both in murine and human beta cells. Finally we will employ a robotized screening to identify the signalling pathway mediating protection of cells lacking the protease of interest from proteotoxic stress. We anticipate that our project might help to elucidate how stress cannot only protect cells from damage, but also induce beneficial functional gains. In addition, we hope to identify pharmacological targets suitable for exploiting the protective potential of the UPR in beta cells and possibly other cells and tissues.

细胞的存活和正常功能依赖于普遍表达的信号通路，这些信号通路保护细胞免受蛋白毒性和遗传毒性应激以及由于感染或炎症引起的应激。在这些途径中，未折叠蛋白反应（UPR）保护内质网中的危险蛋白过载对于高度活跃的分泌细胞尤其重要。胰腺β细胞通过UPR的组成型和诱导型参与来科普可变的代谢胰岛素需求。最近的研究结果表明，UPR不仅可以增加胰岛素的折叠和分泌能力，而且还可以通过未知的机制诱导β细胞增殖。我们已经发现，β细胞蛋白酶的缺失上调UPR并在鼠β细胞中诱导强烈的增殖反应。同时，缺乏这种蛋白酶的非肥胖糖尿病小鼠受到保护，免受自身免疫性糖尿病的影响，并且它们的β细胞受到保护，免受T细胞杀伤。本研究的目的将是确定潜在的机制和信号通路，并可能确定应激反应的药理学调节的目标。该项目汇集了高度互补的团队，贡献了i）关于缺乏这种蛋白酶的小鼠和β细胞的大量初步数据，ii）关于β细胞生理学和胰岛素加工的强大专业知识，以及iii）机器人化小分子筛选方法的专业知识。在这个项目中，我们将研究删除这种蛋白酶对β细胞生理学的影响，特别是使用细胞生物学方法监测胰岛素的合成，加工和周转。第二个工作包的目标是分析这种蛋白酶的缺乏如何影响对β细胞的先天性和适应性免疫反应，并特异性地保护它们免受杀伤。此外，我们将研究这种蛋白酶的缺乏如何触发UPR，以及这是如何与β细胞再生，使用细胞生物学，基因组学和蛋白质组学方法。这将在鼠和人β细胞中进行研究。最后，我们将采用自动化筛选来鉴定介导保护缺乏感兴趣的蛋白酶的细胞免受蛋白毒性应激的信号通路。我们预计，我们的项目可能有助于阐明压力如何不仅保护细胞免受损伤，而且还诱导有益的功能增益。此外，我们希望确定适合于利用UPR在β细胞和其他细胞和组织中的保护潜力的药理学靶点。