Type 1 diabetes is a disorder that results from the destruction of the insulin secreting β-cells of the pancreatic islets. The loss of these cells leads to a deficiency in insulin, and the inability of type 1 diabetic patients to regulate blood sugar. Recently, islet transplantation has emerged as a promising therapy for type 1 diabetes, reducing both the complications and the need for insulin injections. Despite the significant progress, less than 10% of islet transplant recipients remain independent of insulin injections after 5 years, indicating failure of the islet grafts. While the reasons behind islet graft failure are poorly understood, factors such as low islet recovery from donor organs and islet loss during transplantation play a significant role. The loss of islets following isolation from donor organs and islet transplantation is mediated by cell death processes triggered by inflammation and lack of oxygen (called hypoxia). Conventional strategies aimed at reducing islet cell death typically target only one of several death pathways or target death during the late-stages after other pathways have already been activated. We have recently revealed that a cellular protein, called SUMO1, is capable of protecting human islet cells from inflammation-induced death. In addition, this protein protects against hypoxiainduced death and affects several different pathways of cell death in other cell types. By targeting multiple pathways of transplantation-induced death, SUMO1 should have greater success in improving transplantation outcomes than conventional strategies targeting individual pathways. In the present proposal, we plan to develop and test in animal models a new SUMO1-based therapy to protect human islet cells from stress after isolation and during transplantation, and to examine the ability of this strategy to prevent graft failure.