Role of Glutamate Dehydrogenase in Carbohydrate, Amino Acid and Energy Metabolism of Neurons

谷氨酸脱氢酶在神经元碳水化合物、氨基酸和能量代谢中的作用

• 批准号: 260140329
• 负责人: Dr. Michaela C. Hohnholt
• 金额: --
• 依托单位: Institut for Lægemiddeldesign og Farmakologi
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/260140329?language=en
• 关键词: Role; Glutamate; Dehydrogenase; Carbohydrate; Amino

Brain neurons are controlling all functions of the body. Although the importance of neuronal health is generally acknowledged, surprisingly little is known about neuronal metabolism. Glutamate dehydrogenase (GDH) is a mitochondrial enzyme that links carbohydrate, amino acid and energy metabolism of cells. The proposed research project will investigate the role of the central enzyme GDH in neuronal metabolism. A mouse with a central nervous system (CNS) specific deletion of the GDH gene Glud1 (CNS-Glud1-/-mice) has been generated recently and the ablation of GDH in the brain of these mice has been confirmed. In vitro cerebellar granule neuron cultures, neuron-astrocyte co-cultures and brain slices from CNS-Glud1-/-mice will be used as model systems. The comparison of data obtained on cell cultures or brain slices from CNS-Glud1-/-mice with control mice will provide information of the role of GDH in neuronal metabolism. Analysis of the metabolism by metabolic mapping employing 13C- and 15N-labeled substrates (e.g. glucose or glutamate) by mass spectrometry and nuclear magnetic resonance spectroscopy will reveal a detailed picture about the role of GDH in neurons. Analysis of the metabolism of neurons in neuron-astrocyte co-cultures and brain slices from CNS-Glud1-/-mice will clarify the role of the neuronal GDH in the metabolic interactions of neurons and astrocytes. Moreover, the importance of GDH for both the glycolytic and mitochondrial neuronal energy production and the neuronal content of the glutamate-containing antioxidant glutathione will be studied. Also, investigations of release and reuptake of the neurotransmitter glutamate will reveal valuable insights into the role of GDH in neurotransmission between neurons. In summary, this project will supply fundamental informations of the role of GDH in neuronal energy metabolism, which will also be essential for further investigations of the contribution of GDH-malfunction in neurological diseases and diseases affecting the brain.

大脑神经元控制着身体的所有功能。虽然神经元健康的重要性是公认的，但令人惊讶的是，人们对神经元代谢知之甚少。谷氨酸脱氢酶（Glutamate dehydrogenase，GDH）是一种连接细胞碳水化合物、氨基酸和能量代谢的线粒体酶。拟议的研究项目将调查中心酶GDH在神经元代谢中的作用。最近已经产生了具有GDH基因Glud 1的中枢神经系统（CNS）特异性缺失的小鼠（CNS-Glud 1-/-小鼠），并且已经证实了这些小鼠脑中GDH的消融。体外小脑颗粒神经元培养物、神经元-星形胶质细胞共培养物和CNS-Glud 1-/-小鼠的脑切片将用作模型系统。从CNS-Glud 1-/-小鼠与对照小鼠的细胞培养物或脑切片上获得的数据的比较将提供GDH在神经元代谢中的作用的信息。通过质谱法和核磁共振光谱法使用13 C-和15 N-标记底物（例如葡萄糖或谷氨酸）进行代谢图谱分析，将揭示GDH在神经元中作用的详细情况。神经元-星形胶质细胞共培养物和CNS-Glud 1-/-小鼠脑切片中神经元代谢的分析将阐明神经元GDH在神经元和星形胶质细胞代谢相互作用中的作用。此外，将研究GDH对糖酵解和线粒体神经元能量产生以及含谷氨酸的抗氧化剂谷胱甘肽的神经元含量的重要性。此外，神经递质谷氨酸的释放和再摄取的调查将揭示有价值的见解GDH在神经元之间的神经传递的作用。总之，该项目将提供GDH在神经元能量代谢中的作用的基本信息，这对于进一步研究GDH功能障碍在神经系统疾病和影响大脑的疾病中的作用也是必不可少的。