Noninvasive PET Imaging of Islet Grafts

描述(由申请人提供)： 胰岛移植为1型糖尿病(T1D)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失去胰岛功能。由于胰岛可以上调其胰岛素的产生，测量血糖、胰岛素C肽的产生和第一时相胰岛素释放只有在相当数量的胰岛已经丢失后才能检测到胰岛功能的丧失。长期以来，人们一直希望可以直接对移植的胰岛进行成像，以便对受体的存活进行纵向监测，从而允许临床医生定制治疗方法，以更有效地支持胰岛移植后的存活。在人类体内移植的胰岛的非侵入性成像现在似乎是可行的，并等待从啮齿动物移植到非人类灵长类动物，然后再移植到人类。 在这个R21提案中，我们将检验以下假设：1)报告基因的病毒载体，随后是光学和微正电子发射断层扫描(MicroPET)成像，为非侵入性监测啮齿动物门脉内胰岛移植后的胰岛细胞量提供了新的方法；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到胰岛排斥反应。我们还将评估病毒感染和长期的PET报告表达和PET成像是否对胰岛移植物有害。如果该项目成功，随后的R33应用程序将尝试将这项技术扩展到非人类灵长类动物肝脏中移植的胰岛的成像。因此，这项提案的结果可能会提供一个基础，从而为改善1型糖尿病患者的护理和治疗提供新的工具。

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.