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

胰岛是一个容纳产生胰岛素的细胞的细胞群落，已知会经历与年龄相关的变化。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有关的疾病。然而，只有少数信号被确定与衰老有关。通过比较年轻动物和年老动物的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。这些迹象包括表达细胞因子TNFα的巨噬细胞的募集和NF-kB信号的激活（一种几乎存在于所有动物细胞类型和感知炎症的组织中的信号通路）。有趣的是，NF-kB的激活不是均匀的，而是在β细胞群中分布不均，这意味着不同的β细胞表现出不同程度的炎症。那些激活NF-kB信号的β细胞也会过早地上调一种抑制其增殖的基因。细胞复制是由逃避NF-kB信号的年龄相关激活的β细胞亚群优先维持的。总之，这些结果记录了老年动物慢性胰岛炎症的发展，高水平的NF-kB信号标志着细胞随着年龄的增长而失去增殖潜力。我们的研究确定组织浸润性免疫细胞是年龄相关炎症的潜在来源。在这项提议中，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信号抑制（其成分失活）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，具有高水平的NF-kB信号在特定条件下赋予β细胞特殊的优势。我们正在探索这个未知的方面，因为这些知识可以帮助改善目前治疗糖尿病的胰岛分离和植入策略。

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.