Mapping the association of beta cell longevity and cell senescence in type 1 diabetes

项目摘要 1型糖尿病(T1D)是由胰腺中产生胰岛素的β细胞功能崩溃引起的。多数 健康胰腺中的β细胞可以和皮质神经元一样老，被归类为长寿细胞。在.期间 T1D，β细胞功能障碍和/或在任何时候都可能发生的自身免疫反应中被破坏 年龄。最近的一项研究将β细胞亚群中β细胞衰老的开始与旁分泌前体联系在一起。 炎症反应，加剧T1Dβ细胞的功能损害和死亡。因此， 清除衰老的T1Dβ细胞足以提高β细胞的存活率并防止T1D的发生。 现在有几项研究表明，T1D患者的胰腺中存在β细胞，这表明 T1D贝塔细胞也可能是长寿的。此外，这些数据表明，特定的贝塔细胞可以存活。 自身免疫攻击，因此能够在人类胰腺中长期存活。不过，目前 未知这些β细胞是如何在恶劣的T1D环境中生存的。它们特定的分子特征可能 为它们的长期生存做好准备也是未知的。该项目将建立既长寿和 利用高分辨转录测序技术研究T1D胰岛β细胞的分子特征 以及T1D小鼠和人类胰腺中单个β细胞的成像技术。这两种技术的结合 这些互补技术将覆盖包含细胞结构和分子的高维数据 转录和蛋白质组水平上的图谱与细胞年龄和寿命。了解测试版的寿命有多长 细胞维持其长期功能和健康将导致促进和保存β细胞的新方法 T1D患者的功能。

Project Summary Type 1 diabetes (T1D) is caused by the functional collapse of insulin-producing beta cells in the pancreas. Most beta cells in the healthy pancreas can be as old as cortical neurons and are classified as long-lived cells. During T1D, beta cells become dysfunctional and/or are destroyed in an auto-immune reaction that can occur at any age. A recent study has linked the onset of beta cell senescence in a sub-set of beta cells with a paracrine pro- inflammatory response that exacerbates the functional impairment and death of T1D beta cells. Accordingly, clearance of senescent T1D beta cells is sufficient to improve beta cell survival and prevent the onset of T1D. Several studies now indicate the presence of beta cells in the pancreas of T1D patients, which indicates that T1D beta cells could also be long-lived. In addition, this data suggests that specific beta cells can survive this auto-immune attack and, thus, are able to survive for long periods in the human pancreas. However, it is currently unknown how these beta cells survive in the harsh T1D environment. Their specific molecular profiles that may predispose them for long-term survival also remain unknown. This project will establish both the longevity and molecular signatures of T1D pancreatic beta cells through utilization of high-resolution transcriptional sequencing and imaging technologies of individual beta cells in the pancreas of T1D mice and humans. The combination of these complementary techniques will overlay this high-dimensional data containing cell structure and molecular profiles at the transcriptional and proteome level with cell age and longevity. Understanding how long-lived beta cells maintain their long-term function and health will lead to new methods to promote and preserve beta cell function in T1D patients.