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.

项目摘要/摘要在胰腺中，胰岛被称为细胞外基质（ECM）的专业蛋白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），为β细胞提供机械和生化线索。在发作期间 T1D，免疫细胞浸润胰腺，ESLET ECM降解，导致β细胞死亡。尽管在T1D中，对ESLET ECM的更改已得到充分记录，这些ECM的作用变化了T1D 发病机理在很大程度上未知。 ECM刚度的变化与胰岛素的变化有关分泌;然而，尚未研究机械结构调节胰岛素分泌的机制浸润的免疫细胞还产生高水平的促炎细胞因子，引起胰岛功能障碍和死亡。虽然一些研究表明浸润的免疫细胞降解了周围 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β-的ECM重塑细胞。 T1D中尚未确定β细胞降解的β细胞降解的作用。我们的总体目标是确定ESLET ECM周日变化对胰岛功能的影响，并确定自动反应性的作用免疫细胞和细胞因子在重塑T1D中重塑EISLE的ECM时强调β细胞。我们将利用一本小说反向热凝胶支架，用层粘连蛋白-10和Col IV功能化，并用封装的小鼠和人胰岛实现这一目标。为了实现这一目标，我们提出了两个具体目标：（1）确定 ECM刚度在胰岛功能和胰岛素分泌动力学上的变化；（2）确定自动反应性的作用 CD4+和CD8+ T细胞和细胞因子在重塑T1D中的ESLEL ECM时强调β细胞。结果这项工作将支持ECM机械性能在调节胰岛功能中的作用，并将定义一个角色 ESLEL周周ECM降解和T1D发病机理中的β细胞。这项工作的创新将提供对治疗T1D的有用洞察力，将有助于改善糖尿病疗法和患者的生活。