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

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。

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.