Inhibiting hypoxia and inflammation-induced damage to improve the outcomes of islet transplantation

Summary We will test methods to reduce the stress response of islets before and during transplantation and determine if these promote islet survival in vivo. Mouse and human islets will be cultured in hypoxic conditions, together with small molecule inhibitors of inflammatory pathways, then transplanted under the kidney capsule of diabetic recipient mice.

Project Details

Islet transplantation is used clinically for replacement of insulin-producing pancreatic beta cells in a subset of patients with type 1 diabetes. During isolation, culture and transport of human islets for transplantation the islets are subjected to a number of stresses that may influence their survival, engraftment and function after transplantation. Analysis of transcriptional changes occurring during islet isolation and culture has provided valuable insights into the stress response of islets initiated by pancreatic islet processing. This has revealed changes in the RNA levels of markers of stress-activated pathways including hypoxia and inflammation.

Aim: We will test methods to reduce the stress response of islets before and during transplantation and determine if these promote islet survival in vivo. Mouse and human islets will be cultured in hypoxic conditions, together with small molecule inhibitors of inflammatory pathways, then transplanted under the kidney capsule of diabetic recipient mice. The minimal mass required for reversal of diabetes will be determined. Stress response gene expression will be measured in the islets and grafts. This work has the potential to be applied to clinical islet transplantation in the future.