The pancreatic islet is surrounded by an extracellular matrix (ECM) composed of laminin, collagen IV, and proteoglycans, that support islet function and viability. Type 1 diabetes (T1D) is characterized by the immunemediated loss of insulin-producing β-cells in the islet. Islet infiltration by activated immune cells results in the degradation of the peri-islet ECM eliminating critical signaling pathways for islet function and survival. The peri-islet ECM may provide a critical barrier to islet infiltration; however, the cellular and molecular contributions to loss of the peri-islet ECM are not well studied, limiting potential therapies targeted at this critical step in T1D. Furthermore, understanding the mechanisms underlying ECM regulation of islet function and how loss of these interactions affects β-cell survival in T1D is critical to understanding and halting T1D pathogenesis. The goal of this study is to determine the respective contributions of immune cells and β-cells to loss of the peri-islet ECM and determine how changes in the peri-islet ECM impact β-cell survival in the context of T1D. We propose 2 aims to achieve this goal: 1) Determine the specific contributions of CD4+ and CD8+ immune cells in degradation of the peri-islet ECM and loss of β-cell mass ECM in T1D, and 2) Determine the contributions of stressed β-cells in degradation of the peri-islet ECM and loss of β-cell mass ECM in T1D. Experiments for both aims will utilize human pancreas sections from the healthy controls, auto-antibody positive donors at risk of developing T1D, and donors with established T1D. The results from this project will define a new for changes in the peri-islet ECM in contributing to decreased islet survival in T1D and will provide novel therapeutic targets to halt immune infiltration of the islet and improve islet survival in T1D.