The role of the peri-islet extracellular matrix in islet function and the pathogenesis of type 1 diabetes

项目总结/摘要 在胰腺中，胰岛被称为细胞外基质（ECM）的特殊蛋白质支架包围， 调节细胞存活和胰岛素分泌。胰岛周围的ECM主要由层粘连蛋白-10和 IV型胶原（COL IV），其为β细胞提供机械和生物化学线索。发作期间 T1 D时，免疫细胞浸润胰腺，胰岛周围ECM降解，导致β细胞死亡。而 胰岛周围ECM的变化在T1 D中已有充分的记载，这些ECM变化对T1 D的作用 发病机制在很大程度上是未知的。ECM硬度的变化与胰岛素水平的变化相关。 然而，尚未研究机械转导调节胰岛素分泌的机制 在小岛上。浸润的免疫细胞还产生高水平的促炎细胞因子，引起胰岛细胞增生。 功能障碍和死亡。虽然一些研究表明，浸润的免疫细胞降解胰岛周围 ECM，最近的一项研究表明，β-细胞与巨噬细胞的相互作用诱导ECM重塑的β- cell.β细胞降解胰岛周围ECM的作用在T1 D中尚未确定。我们的总体目标是 确定胰岛周围ECM的变化对胰岛功能的影响，并确定自身反应的作用。 免疫细胞和细胞因子应激β细胞在T1 D中重塑胰岛周围ECM中的作用。我们将利用一本小说 用层粘连蛋白-10和COL IV功能化的反向热凝胶支架， 岛来实现这一目标。为了实现这一目标，我们提出了两个具体目标：（1）确定 ECM刚度的变化对胰岛功能和胰岛素分泌动力学的影响;（2）确定自身反应性的作用。 CD 4+和CD 8 + T细胞和细胞因子应激的β细胞在T1 D中重塑胰岛周围ECM中的作用。的结果 这项工作将支持ECM机械特性在调节胰岛功能中的作用，并将定义ECM的作用。 β细胞在胰岛周围ECM降解中的作用及在T1 D发病机制中的作用。这项工作的创新将提供 这是治疗T1 D的有用见解，将有助于改善糖尿病治疗和患者的生活。

PROJECT SUMMARY/ABSTRACT In the pancreas the islet is surrounded by a specialized protein scaffold called the extracellular matrix (ECM) that regulates cell survival and insulin secretion. The ECM surrounding the islet consists mainly of laminin-10 and type IV collagen (COL IV) which provide mechanical and biochemical cues to the β-cells. During the onset of T1D, immune cells infiltrate the pancreas and the peri-islet ECM is degraded, leading to β-cell death. While changes to the peri-islet ECM have been well documented in T1D, the role of these ECM changes to T1D pathogenesis are largely unknown. Changes to ECM stiffness have been correlated to changes in insulin secretion; however, the mechanisms of mechanotransduction regulating insulin secretion have not been studied in the islet. Infiltrating immune cells also produce high levels of pro-inflammatory cytokines that cause islet dysfunction and death. While some studies have suggested that infiltrating immune cells degrade the peri-islet ECM, a recent study has shown that β-cell interactions with macrophages induces ECM remodeling by the β- cell. A role for the β-cell degrading the peri-islet ECM has not been established in T1D. Our overall goal is to determine the effect of changes in peri-islet ECM on islet function and to determine the role of autoreactive immune cells and cytokine stressed β-cells in remodeling the peri-islet ECM in T1D. We will utilize a novel reverse thermal gel scaffold functionalized with laminin-10 and COL IV with encapsulated mouse and human islets to accomplish this goal. Towards this goal we propose two specific aims: (1) Determine the effect of changes in ECM stiffness on islet function and insulin secretion dynamics; (2) Determine the role of autoreactive CD4+ and CD8+ T-cells and cytokine stressed β-cells in remodeling the peri-islet ECM in T1D. The results from this work will support a role for ECM mechanical properties in regulating islet function and will define a role for the β-cell in peri-islet ECM degradation and in the pathogenesis of T1D. The innovation of this work will provide useful insight into treating T1D and will help to improve diabetes therapies and the lives of patients.