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

项目摘要 1型糖尿病（T1 D）是由胰腺中产生胰岛素的β细胞的功能崩溃引起的。最 健康胰腺中的β细胞可以与皮层神经元一样老，并被归类为长寿细胞。期间 T1 D，β细胞变得功能障碍和/或在自身免疫反应中被破坏，这可能发生在任何 年龄最近的一项研究将β细胞亚群中β细胞衰老的发生与旁分泌促衰老因子联系起来。 炎症反应加剧T1 D β细胞的功能损伤和死亡。因此，委员会认为， 清除衰老的T1 D β细胞足以改善β细胞存活并防止T1 D的发作。 现在有几项研究表明T1 D患者胰腺中存在β细胞，这表明， T1 D β细胞也可能是长寿的。此外，这些数据表明，特定的β细胞可以在这种情况下存活。 自身免疫攻击，因此能够在人胰腺中长期存活。但目前 目前尚不清楚这些β细胞如何在T1 D的恶劣环境中存活。它们的特定分子特征 使他们更容易长期生存也仍然未知。该项目将建立两个长寿和 通过高分辨率转录测序的T1 D胰腺β细胞的分子特征 以及T1 D小鼠和人类胰腺中单个β细胞的成像技术。的组合 这些互补技术将覆盖包含细胞结构和分子的这种高维数据 在转录和蛋白质组水平与细胞年龄和寿命的概况。了解beta寿命如何 细胞保持其长期功能和健康将导致新的方法来促进和保护β细胞 T1 D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.