组合应用NMR代谢组学和生物医学技术研究阿尔茨海默病的分子机制及其与糖尿病脑病的代谢关联

基于1H NMR的代谢组学可以从整体上研究疾病的代谢特征，然而疾病发生发展的确切调控途径等细节信息却无法获得。本项目拟在前期研究基础上，首先采用基于1H NMR的代谢组学技术分析阿尔茨海默病(AD)发生发展中各脑区代谢变化特征，阐明该病进展中的代谢调控网络，以及胶质细胞与神经元间的谷氨酰胺-谷氨酸-γ氨基丁酸神经递质代谢循环，然后借助免疫组化、蛋白质免疫印迹等生物医学技术检测神经元凋亡、胶质细胞增生、和代谢调控途径上的关键酶或蛋白的含量变化。综合分析，阐明AD发生发展的分子机制及其与糖尿病脑病的代谢关联。本项目将系统建立组合应用1H NMR代谢组学和生物医学技术的脑代谢机制研究方法，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AD，发现药物新靶点用于AD治疗提供理论基础，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。

1H NMR-based metabonomics holds a potential for investigation of whole metabolic profiling of diseases, but the detailed information on the regulation of pathological development cannot be obtained. Based on our promising preliminary work, we attempt to study the metabolic changes in brain compartments during the development of Alzheimer's disease (AD), elucidate the metabolic regulatory networks in disease development, and investigate the metabolic pathway of the glutamine-glutamate-GABA cycle between the astrocytic and neuronal compartments. Furthermore, the neuronal apoptosis, gliocyte proliferation and the change of the key enzymes or proteins in the metabolic pathways will be explored by immunohistochemistry, western blot and other biomedical technologies. This comprehensive analysis facilitates the understanding of the molecular mechanism of AD and the metabolic correlation with diabetic encephalopathy. The systematic approach by combining 1H NMR-based metabonomics and biomedical technique can be applied for exploring mechanisms of cerebral metabolism, which achieves complementary advantages between the modern integrated study and the classic target research, and thereby provides a theoretical basis for early prevention and diagnosis of AD as well as identification of its new drug targets. In addition, our research proposes a novel method to investigate the metabolic mechanism and treatment of other nervous system diseases.