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

• 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
• 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

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，胰岛被一种称为细胞外基质(ECM)的特殊蛋白质支架所包围 调节细胞存活和胰岛素分泌。胰岛周围的细胞外基质主要由层粘连蛋白-10和 IV型胶原(Col IV)，为β细胞提供机械和生化信号。在……开始期间 T1d时，免疫细胞渗入胰腺，胰岛周围细胞外基质降解，导致β细胞死亡。而当 胰岛周围ECM的变化在T1D中得到了很好的记录，这些ECM变化在T1D中的作用 发病机制很大程度上还不清楚。细胞外基质硬度的变化与胰岛素的变化有关 然而，机械转导调节胰岛素分泌的机制还没有被研究。 在小岛上。渗入的免疫细胞也会产生高水平的促炎细胞因子，从而导致胰岛 功能障碍和死亡。虽然一些研究表明，渗入的免疫细胞会使胰岛周围退化 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-1诱导细胞外基质重塑。 手机。在T1D中，β细胞降解胰岛周围细胞外基质的作用尚未确立。我们的总体目标是 确定胰岛周围细胞外基质变化对胰岛功能的影响以及自身反应的作用 免疫细胞和细胞因子刺激β细胞重塑T1D大鼠胰岛周围细胞外基质。我们将利用一本小说 层粘连蛋白-10和胶原蛋白IV功能化反向热凝胶支架与包裹的小鼠和人 实现这一目标的小岛。为了实现这一目标，我们提出了两个具体目标：(1)确定 细胞外基质硬度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 CD_4~+、CD_8~+T细胞和细胞因子刺激的β-细胞在T1D胰岛周细胞外基质重塑中的作用。结果来自于 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细胞在胰岛周围细胞外基质降解及T1D发病机制中的作用这项工作的创新将为 对治疗T1D有有用的见解，并将有助于改善糖尿病治疗和患者的生活。