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

胰岛周围细胞外基质在胰岛功能和 1 型糖尿病发病机制中的作用

基本信息

批准号：
10538267
负责人：
Chelsea Garcia Johansen
金额：
$ 4.43万
依托单位：
COLORADO SCHOOL OF MINES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538267
关键词：
3-Dimensional Affect Beta Cell Biochemical Biocompatible Materials Biology Biomedical Engineering CD8-Positive T-Lymphocytes Calcium Cathepsins Cell Communication Cell Death Cell Survival Cells Cessation of life Collagen Type IV Cues Development Diabetes Mellitus Disease Encapsulated Enzymes Extracellular Matrix Extracellular Matrix Degradation Functional disorder Gel Gene Expression Glucose Glycolysis Goals Human Immune Immunohistochemistry In Vitro Inbred NOD Mice Infiltration Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Interferon Type II Interferon-alpha Interferons Interleukin-1 beta Islets of Langerhans Knowledge Matrix Metalloproteinases Measures Mechanics Metabolic Metabolism Mus Pancreas Pathogenesis Patients Population Research Research Personnel Rho-associated kinase Role Scaffolding Protein Signal Pathway Signal Transduction Splenocyte Stains Stress System T-Lymphocyte TNF gene Time Training Transferase Tumor-infiltrating immune cells Variant Work autoreactivity career cytokine diabetes mellitus therapy diabetes pathogenesis diabetic improved in vitro Model innovation insight insulin dependent diabetes mellitus onset insulin secretion islet kinase inhibitor laminin-10 macrophage mechanical properties mechanotransduction mimetics novel scaffold skills

项目摘要

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.

项目概要/摘要在胰腺中，胰岛被一种称为细胞外基质 (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 型胶原蛋白 (COL IV) 在β细胞出现期间提供机械和生化信号。 T1D 中，免疫细胞浸润胰腺，胰岛周围 ECM 降解，导致 β 细胞死亡。 T1D 中胰岛周围 ECM 的变化已得到充分记录，这些 ECM 变化对 T1D 的作用 ECM硬度的变化与胰岛素的变化有关。然而，机械传导调节胰岛素分泌的机制尚未被研究。胰岛中的浸润免疫细胞也会产生高水平的促炎细胞因子，从而导致胰岛病变。虽然一些研究表明浸润的免疫细胞会降解胰岛周围。 ECM，最近的一项研究表明，β 细胞与巨噬细胞的相互作用通过 β-细胞诱导 ECM 重塑 β 细胞降解胰岛周围 ECM 的作用尚未在 T1D 中确定。确定胰岛周围 ECM 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的 β 细胞在 T1D 中重塑胰岛周围 ECM 中我们将利用一种新颖的方法。用层粘连蛋白-10 和 COL IV 功能化的反向热凝胶支架，并封装小鼠和人类为了实现这一目标，我们提出了两个具体目标：（1）确定效果。 ECM硬度的变化对胰岛功能和胰岛素分泌动力学的影响；（2）确定自身反应的作用； CD4+ 和 CD8+ T 细胞以及细胞因子应激的 β 细胞在重塑 T1D 胰岛周围 ECM 中的作用。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 β 细胞在胰岛周围 ECM 降解和 T1D 发病机制中的作用，这项工作将提供创新。治疗 T1D 的有用见解，将有助于改善糖尿病治疗和患者的生活。