Noninvasive PET Imaging of Islet Grafts

描述（由申请人提供）： 胰岛移植为1型糖尿病（T1 D）提供了一种潜在的治疗方法，可以使血糖水平正常化并避免糖尿病相关并发症的发生。尽管最近在胰岛分离和免疫抑制方案方面取得了进展，但许多胰岛受体在移植后逐渐丧失胰岛功能。由于胰岛可以上调其胰岛素的产生，因此血糖、胰岛素C肽产生和第一时相胰岛素释放的测量仅在大量胰岛已经丧失之后才检测到胰岛功能的丧失。长期以来，人们一直希望移植的胰岛可以直接成像，以便可以在受体中纵向监测它们的存活，从而使临床医生能够定制治疗方法，以更有效地支持移植后的胰岛存活。对人类移植胰岛的非侵入性成像现在似乎是可行的，并等待从啮齿动物到非人类灵长类动物，然后到人类的翻译。 在这项R21提案中，我们将测试以下假设：1）报告基因的病毒递送，随后进行光学和微正电子发射断层扫描（microPET）成像，提供了新的模式，以非侵入性监测啮齿动物门静脉内胰岛移植后的胰岛细胞质量; 2）光学和microPET成像可以比血糖和C肽水平的测量更早地检测胰岛排斥反应。我们还将评估病毒感染和长期PET报告基因表达和PET成像是否对胰岛移植物有害。如果该项目成功，随后的R33应用将尝试将该技术扩展到非人类灵长类动物肝脏中移植胰岛的成像。因此，这项建议的结果可能会提供一个基础，这将导致新的工具，以改善1型糖尿病患者的护理和治疗。

DESCRIPTION (provided by applicant): Islet transplantation offers a potential treatment for type 1 diabetes (T1D) that could normalize blood glucose levels and circumvent the development of diabetes-associated complications. Despite recent advances in islet isolation and immunosuppressive regimens, many islet recipients gradually lose islet function after transplantation. Because islets can up-regulate their production of insulin, measurements of blood glucose, insulin C-peptide production and 1st phase insulin release detect the loss of islet function only after a significant number of islets have already been lost. It has long been hoped that transplanted islets could be directly imaged, so that their survival could be longitudinally monitored in recipients, allowing clinicians to tailor therapies to more effectively support islet survival post-transplantation. The noninvasive imaging of transplanted islets in humans now appears to be feasible, and awaits translation from rodents to nonhuman primates, and then to humans. In this R21 proposal we will test the hypotheses that; 1) the viral delivery of reporter genes, followed by optical and micro-positron emission tomography (microPET) imaging, provide new modalities to noninvasively monitor islet cell mass after intraportal islet transplantation in rodents and; 2) optical and microPET imaging can detect islet rejection earlier than measurements of blood glucose and C-peptide levels. We will also evaluate whether viral infection and long-term PET reporter expression and PET imaging is deleterious to the islet graft. If this project is successful, a subsequent R33 application will attempt to extend this technology to the imaging of transplanted islets in the liver of non-human primates. Thus, the results of this proposal may provide a foundation that will lead to new tools for improving the care and treatment of those with type 1 diabetes.