Defining the role of NF-kB signaling as a key driver of pancreatic beta-cell aging and heterogeneity

定义 NF-kB 信号传导作为胰腺 β 细胞衰老和异质性关键驱动因素的作用

• 批准号: 415464617
• 负责人: Professor Dr. Nikolay Ninov, Ph.D.
• 金额: --
• 依托单位: Zentrum für Regenerative Therapien Dresden - CRTD
• 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/415464617?language=en
• 关键词: Defining; role; NF; kB; signaling

The pancreas islet, a cellular community that hosts the insulin-producing beta cells, is known to undergo age-related changes. In particular, aging is associated with a reduction in the renewal capacity of beta-cells and type 2 diabetes is an age-related disease. However, only a handful of signals have been identified in connection with ageing. By comparing beta cells from younger and older animals, my group showed that the aging islets show signs of chronic inflammation. These signs include recruitment of macrophages that express the cytokine TNFα and the activation of NF-kB signaling (a signaling pathway found in virtually all animal cell types and tissues that senses inflammation). Interestingly, the activation of NF-kB is not uniform but heterogeneously distributed across the beta-cell population, meaning that different beta-cells exhibit different levels of inflammation. Those beta-cells that activate NF-kB signaling at higher levels also upregulate prematurely a gene that inhibits their proliferation. Cell replication is preferentially maintained by a subpopulation of beta-cells that escape the age-related activation of NF-kB signaling. Altogether, the results document the development of chronic islet inflammation in older animals, with high levels of NF-kB signaling marking the cells that lose proliferative potential with age.Our study identified tissue-infiltrating immune cells as a potential source of age-related inflammation. In this proposal, we plan to understand the specific signals that the immune cells release, which will help define their role in regulating islet inflammation. Furthermore, we will test whether pharmacological and genetic NF-kB signaling inhibition (inactivation of its components) can rejuvenate the aging islet in order to increase beta-cell renewal. Finally, some of our new preliminary data indicate that having high levels of NF-kB signaling confer a particular advantage to the beta-cells under specific conditions. We are exploring this unknown aspect because the knowledge could help improve current strategies for islet isolation and engraftment for diabetes-treatment.

众所周知，胰岛是一个细胞群落，它是产生胰岛素的β细胞的宿主，会发生与年龄相关的变化。特别是，衰老与β细胞更新能力的降低有关，2型糖尿病是一种与年龄相关的疾病。然而，只有少数信号与衰老有关。通过比较年轻和年长动物的β细胞，我的研究小组发现，衰老的胰岛显示出慢性炎症的迹象。这些体征包括表达细胞因子TNFα的巨噬细胞的募集和NF-kB信号传导（一种在几乎所有动物细胞类型和组织中发现的感知炎症的信号传导途径）的激活。 有趣的是，NF-kB的激活在β细胞群中不是均匀的，而是不均匀分布的，这意味着不同的β细胞表现出不同的炎症水平。那些以较高水平激活NF-kB信号的β细胞也过早地上调了抑制其增殖的基因。细胞复制优先由逃避年龄相关的NF-κ B信号转导激活的β细胞亚群维持。总而言之，这些结果证明了老年动物慢性胰岛炎症的发展，高水平的NF-kB信号标志着随着年龄的增长而失去增殖潜力的细胞。 在这项提案中，我们计划了解免疫细胞释放的特定信号，这将有助于确定它们在调节胰岛炎症中的作用。此外，我们将测试是否药理学和遗传NF-kB信号传导抑制（其组分的失活）可以使老化的胰岛恢复活力，以增加β细胞更新。 最后，我们的一些新的初步数据表明，在特定条件下，具有高水平的NF-kB信号传导赋予β细胞特别的优势。我们正在探索这个未知的方面，因为知识可以帮助改善目前的策略，胰岛分离和移植治疗糖尿病。