基于核磁共振的代谢组学研究多脑区代谢通路参与帕金森病发生发展的机制

Parkinson’s disease (PD) has a marked adverse impact on human health due to its high prevalence. Thus, it is of great importance to further discover metabolic mechanisms of PD development for improving its therapy and prevention. In the present project, we will analyze the characteristic metabolic changes in different brain regions (e.g. striatum and mesencephalon) during the development and onset of PD using nuclear magnetic resonance (NMR)-based metabonomics. Metabonomic results will elucidate metabolic pathways in different brain regions, Gln-Glu-GABA circle between astrocytes and neurons as well as their differences and relationships between different brain regions. Furthermore, we will investigate metabolic biomarkers in vulnerable brain region and metabolic pathways in cerebrospinal fluid of PD patients to explore the metabolic difference between human subject and animal model. In addition, the key enzymes or proteins that cause metabolic disturbance will be identified by metabolite database and further validated through molecular biology techniques including Western blot and RT-PCR. The expected results aim to develop a systematical NMR-based metabonomic approach for the investigation of molecular and metabolic mechanisms underlying PD and elucidate the effects of metabolic regulations in different brain regions during the development and onset of PD. The present project attempts to complement and unify the outcome from fundamental research and clinical application. The proposed method provides not only a theoretical foundation for diagnosis, therapy and prevention of PD, but also a new way to study metabolic mechanisms and therapies of other neurological diseases.

帕金森病(Parkinson’s disease, PD)发病率高，危害严重。深入认识PD的代谢机制将有助于其预防和治疗。本项目采用基于核磁共振的代谢组学分析PD发生发展中纹状体、中脑等不同脑区的代谢变化特征，阐明PD进展中各脑区的代谢通路及其变化规律，胶质细胞与神经元间的Gln-Glu-GABA代谢循环，以及不同脑区间的差异与关联；结合代谢物数据库寻找导致代谢调控紊乱的关键酶或蛋白，借助Western blot免疫印迹和RT-PCR等分子生物学技术进行筛选和验证。预期结果将系统建立基于1H NMR的代谢组学研究PD的新技术，阐明各脑区的代谢通路参与PD发生发展的机制，初步实现现代的整体研究与经典的靶点研究间的互补与统一，为早期预防和诊断PD，发现治疗PD的药物新靶点提供理论基础，同时也为其它神经系统疾病的代谢机制与治疗研究提供新思路。

帕金森病(Parkinson’s disease，PD)是由于黑质致密部中多巴胺能神经元的进行性丧失而导致纹状体中多巴胺耗竭的一种年龄相关的神经退行性疾病，异动症(L-dopa induced dyskinesia，LID)是其最常见的远期并发症之一。随着人口老龄化速度的不断加快，找寻新的治疗策略迫在眉睫。成纤维细胞生长因子21(FGF21)，是一种主要由肝脏分泌，能够调控机体物质代谢的新型内分泌激素，在肥胖患者和动物模型中都被证明能够调节能量平衡、葡萄糖和脂质代谢。研究表明FGF21能够通过神经轴参与调控能量代谢，也可以通过外周调控来有效的改善脑功能障碍。.我们应用基于1H NMR代谢组学技术分析帕金森病发生发展中的代谢变化特征，阐明疾病状态下脑内时间与网络上的代谢模式的变化规律。结果表明，PD和LID大鼠脑区存在特异性的代谢物轮廓，指出中脑-纹状体代谢紊乱可能会介导疾病的进展和治疗，神经递质代谢紊乱尤其是Glu-Gln-GABA循环受损可能是诱发异动症的病理基础；外源性腹腔注射补充FGF21，能够明显改善帕金森小鼠的运动缺陷以及学习记忆功能障碍，且FGF21可以明显改善帕金森小鼠脑区代谢模式的紊乱。.通过本项目实施，明确PD发生发展过程中脑区及时间特异性的代谢模式，对更好地理解帕金森病的发病机制及其早期诊断与治疗具有重要意义。此外，FGF21对PD运动功能障碍、增强学习记忆功能及代谢模式的调控也为提高帕金森患者的生活质量，降低家庭与社会的负担提供了一种新的个性化治疗药物研发思路。