精神分裂症相关区域分子探针的研制及受体间相互作用影响的研究

On the basis of the study of NMDA receptor molecular probes and the pathogeny of schizophrenia, this project brought up the hypothesis "neurotransmitter imbalance"：The synergy of each receptor makes up a complex system with abundant neurotransmitters, this system is normally in equilibrium, while once the balance were broken, neurotransmitters would be abnormal, abnormality of neurotransmitters in different regions of brain would display different symptom of schizophrenia. In this project, several technetium labeling PQQ analogues----region-specific molecular probe were developed to image region-specific distribution of neurotransmitter in the brain of schizophrenic models. The molecular probes of dopamine receptor, 5-hydroxytryptamine receptor and glutamate recptor developed by our group and other groups in our institute could be used to analyze the relationship between interaction of receptors and schizophrenia with molecular nuclear medicine technology. Interaction of different receptors and influence on signal pathway were studied with technology of molecular biology and cell biology such as construction of plasmid, cell transfection and biofluorescence resonance energy transfer (BRET) analysis. This project adopted the methods of multi-receptors integration research different from formerly one-receptor research, would help to unlock the mysteries of causes of mental illness, enhance our international competitiveness in research about schizophrenia.

本项目在研究NMDA 受体分子探针及精神分裂症病因的基础上，提出精神分裂症"神经递质失衡"之假说：脑内各受体协同作用，组成富含多种神经递质的复杂体系，脑功能正常状态体系处于平衡，一旦平衡失调引起脑内某区域神经递质异常，不同区域的神经递质异常表现为精神分裂症的不同症状。本项目设计区域分子探针--99mTc标记的PQQ（R）类似物，评价精神分裂症动物模型脑内区域神经递质分布的特异性；利用本课题组及我所研制成功的三大受体分子探针，采用放射自显影和竞争结合分析研究受体相互作用与精神分裂症的关系；并通过质粒构建、细胞转染、生物荧光共振能量转移（BRET）分析等细胞生物学与分子生物学手段研究不同受体相互作用及其对信号通路的影响。本项目从单一受体转变到多系统集成研究，有助于进一步解开精神疾病发病机理的迷团，提升我国在精神分裂症研究领域在国际上的竞争力。

随着经济的快速发展，精神疾病发病率持续增加，精神分裂症的发病机制非常复杂。本项目设计并研制了新的锝标记的精神分裂症区域分子探针99mTc-PQQ系列化合物，采用甘露醇开放血脑屏障，提高了放射性配体的进脑量。采用磁固相纳米技术分析了精神分裂症脑部神经递质区域分布特点，探索了精神分裂症受体之间的作用，为“精神分裂症平衡体系失调神经递质异常”假说提供了实验依据。并对PQQ改善MK-801所致精神损伤的机制进行了研究，发现PQQ对MK801诱导的刻板和共济失调行为具有明显的抑制作用，与D-丝氨酸联合给药，能够显著改善因MK801诱导而导致的社会记忆能力损伤。相关机理研究发现PQQ可以逆转MK-801所引起的前额叶皮层、海马等部位的Akt、GSK-3β蛋白磷酸化水平的变化。在脑功能受体研究中发现可能存在新的药物作用机制：PQQ联合D-丝氨酸直接结合不饱和位点从而激活甘氨酸位点。由此，我们有了新的思路：对NMDA受体的共激动可能是治疗精神分裂症认知功能障碍的新的有效方法。为中枢神经系统疾病机理研究和药物发现提供新的思路。