항산화 효과 증진을 위한 췌장 소도 세포 공학

Abstract

Type 1 diabetes mellitus (T1DM) is characterized by an autoimmune disease which auto-reactive T cells destroy the patient’s own beta cells, thereby causing insufficient of insulin and thus inducing hyperglycemia. Currently, patients with T1DM use lifelong insulin administration to control blood glucose levels. Although insulin therapy maintains normoglycemia in diabetic patients, there are still frequent unpredictable hypoglycemia. The unstable blood glucose control may cause many complications. Many recent studies demonstrated that pancreatic islet transplantation is an ideal remedy for treatment of type 1 diabetes mellitus. It not only provides freedom from insulin injection, but also is able to improve glycemic control with less hypoglycemia and nephropathy. Although islet transplantation has many advantages for diabetic patients, there are still some obstacles that limit long-term survival of transplanted islets. The major hurdle is hypoxia-induced graft failure. More than 70% of islet grafts undergo oxidative stress after transplantation. The hypoxia causes the excessive generation of reactive oxygen species (ROS). The ROS molecules damage islets by oxidation of proteins, lipids, and nucleic acids. In addition, the ROS molecules activate macrophages and then lead to secrete toxic cytokines, such as TNF-α (tumor necrosis factor-alpha), IL-1β (Interleukin-1 beta), and IFN-γ (Interferon gamma), thereby causing hypoxia-induced inflammatory responses. Consequently, transplanted islets are gradually rejected under hypoxic condition. To overcome these limitations, herein, I presented several kinds of strategies that can improve the hypoxic resistance of transplanted islets as following: (1) Tat-MT fusion protein delivery protected islets from hypoxic stress. (2) Administration of bilirubin nanoparticles (BRNPs) showed potent anti-oxidative and anti-inflammatory effects in islet transplantation. (3) Transduction of RGD-incorporated adenovirus encoding HO1 effectively attenuated the release of HMGB1 protein, a key inflammatory mediator, under hypoxic stress condition. I further developed the immune-isolative microfiber entrapping islets to reduce the host immune response after transplantation. In addition, I identified an islet homing peptide that can be used as a molecular imaging ligand to monitor the transplanted islets. Taken together, combination of these novel strategies would be a potent clinical remedy for successful islet transplantation.