基于分子影像活体监测PD大鼠脑内移植hESC-RPE细胞存活状态及原神经元变化的相关机制研究

Parkinson’s disease (PD) is chiefly characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra induced a deficiency of dopamine in striatum. Cell transplantation therapy is a promising method for the treatment of PD in the future. However, there is no effective and noninvasive means which could be applied to monitor the survival, proliferation, and differentiation of transplanted cells and the change of host neurons after cell transplantation in vivo. On the basis of our prior studies which included PD metabolic brain networks, dopamine transporter and neuroinflammation molecular probes, and human retinal pigment epithelial (hRPE) cells therapy in PD patients, we propose to investigate whether 18F-P3BZA PET/CT and multimodality molecular imaging could be used for monitoring the survival of human embryonic stem cells (hESC) derived RPE cells in the brain of PD rats after transplantation, as well as the changes of host neurons, finally to determine the underlying mechanisms. Exploring the effective transplantation methods and the effectiveness of immunosuppressive combination therapy were included too. The objective of this project is to further confirm the effectiveness and effective method of hESC-RPE cells therapy for PD rats, and establish a set of molecular imaging evaluation system for monitoring hESC-RPE cells therapy in PD in vivo, which would provide a scientific basis for the future clinical application.

帕金森病（PD）以黑质区多巴胺（DA）神经元缺失导致纹状体DA水平下降为病理特征，细胞替代治疗是未来PD治疗的方法之一。然而，细胞替代治疗后移植细胞的存活、分化，原神经元的变化等目前尚无有效无创的活体监测方法。本项目拟在既往PD脑葡萄糖代谢网络、多巴胺转运体（DAT）、神经炎症分子探针及人视网膜色素上皮（hRPE）细胞治疗PD临床研究基础上，采用18F-P3BZA PET/CT监测PD大鼠脑内移植人胚胎干细胞（hESC）来源的RPE细胞的存活情况，通过多模态显像评价宿主原神经元代谢网络、DAT和炎症变化，实现活体监测 PD大鼠脑内移植细胞存活状态及对脑内原神经元的影响，探明hESC-RPE细胞治疗PD的相关机制，探索有效移植方式和免疫抑制联合治疗的有效性。本项目的实施将建立hESC-RPE细胞治疗PD活体分子影像评估体系，从而为其有效临床应用提供科学依据。

帕金森病（PD）以黑质区多巴胺（DA）神经元缺失导致纹状体多巴胺水平下降为主要病理特征，因此细胞移植治疗可能是未来PD治疗的优选。本课题在既往PD脑葡萄糖代谢网络、多巴胺转运体（DAT）、神经炎症分子探针以及hRPE治疗PD临床研究基础上，成功合成神经黑色素靶向的PET分子探针18F-P3BZA，标记方法稳定，未衰减校正的平均放化产率为15%，放化纯度≥99%。确定了无框架立体定向Ommaya囊脑室内植入干细胞是治疗PD的最佳移植方式。应用18F-P3BZA Micro PET/CT显像活体监测PD大鼠移植治疗后脑内存活的hRPE细胞功能状态。通过18F-FDG、18F-FPCIT和18F-DPA714 PET影像评估干细胞移植对宿主大脑神经元的作用，建立PD 干细胞移植多模态分子影像评估体系。3例临床研究病例初步结果提示移植术后3个月PD患者尾状核、壳核的不对称指数（AI）呈下降趋势，两侧纹状体区域的壳核/尾状核比值（PCR）增大，尾状核、壳核的AI与UPDRS显著正相关，存在客观的脑纹状体区域多巴胺神经递质的改善。PET/MR多模态影像可作为评价干细胞治疗帕金森病的客观影像学指标。