GLUTAMIC DEHYDROGENASE IN NEUROLOGIC DISORDERS

谷氨酸脱氢酶在神经系统疾病中的作用

• 批准号: 3397205
• 负责人: ANDREAS PLAITAKIS
• 金额: $ 28.14万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-07 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3397205
• 关键词: Xenopus; aminoacid metabolism; brain; central nervous system disorders; degenerative motor system disease; egg /ovum; electrofocusing; electrophoresis; enzyme activity; enzyme biosynthesis; enzyme structure; epidemiology; female; genetic markers; genetic transcription; glutamate dehydrogenase; glutamates; human genetic material tag; human subject; isozymes; kidney; liver; lymphocyte; messenger RNA; molecular cloning; molecular pathology; nucleic acid sequence; nucleic acid structure; point mutation; polymerase chain reaction; posttranslational modifications; protein biosynthesis; protein sequence; protein structure; restriction fragment length polymorphism; tissue /cell culture

Glutamate dehydrogenase(GDH) has been shown to be significantly reduced in patients with heterogenous neurological disorders with system atrophy in which the metabolism of glutamate is abnormal. There is evidence that distinct GDH abnormalities, probably resulting from gene mutations, may underlie the clinical and genetic heterogeneity associated with reduced enzymatic activity. Thus, multiple GDH isoproteins have been shown to exist in human brain, some of which differ in their N-terminus. These were found to be differentially reduced in quantity and altered in catalytic properties and function in the brain of patients with 2 distinct types of neurodegenerative disorders. In addition, multiple mRNAs of different size have been shown to exist in various mammalian tissues, including human brain as well as multiple GDH genes. However, it is still unclear whether the different sized mRNAs and GDH isoproteins are specified by nonidentical genes or result from one functional gene by alternate splicing and post- translational modification processes,respectively. To answer these questions and further elucidate the role of the enzyme in the biology of the nervous system in health and disease, we propose: 1) To further characterize the GDH isoproteins in brain and cultured lymphocytes of patients with various degenerative neurological disorders and controls. 2) To further characterize the GDH-specific mRNAs in controls and neurologic patients and determine whether they represent distinct species. 3) To isolate and characterize GDH specific cDNA from cultured lymphocytes of neurologic patients with abnormal GDH in order to search for the gene defect responsible for the altered enzyme activity. 4) To express mutant cDNAs in heterologous cell systems in order to characterize the enzyme produced and explore causality of these mutations to human neurodegenerations. In addition, the structure, organization and function of the of the human GDH genes will be determined. These studies will lay the ground work for further analysis of the above disorders at the genomic DNA level.

谷氨酸脱氢酶 (GDH) 已被证明显着降低 患有异质性神经系统疾病并伴有系统萎缩的患者 谷氨酸代谢异常。有证据表明 明显的 GDH 异常可能是由基因突变引起的 是与减少相关的临床和遗传异质性的基础 酶活性。因此，多种 GDH 同种蛋白已被证明存在 人脑中的一些神经元的 N 末端有所不同。这些被发现了 数量上有差别地减少并催化上发生改变 患有两种不同类型的患者大脑的特性和功能 神经退行性疾病。此外，多个不同大小的mRNA 已被证明存在于多种哺乳动物组织中，包括人类 大脑以及多个 GDH 基因。但目前尚不清楚是否 不同大小的 mRNA 和 GDH 同工蛋白由不相同的指定 基因或由一个功能基因通过交替剪接和后处理产生的结果 分别是翻译修饰过程。 为了回答这些问题并进一步阐明酶在 神经系统在健康和疾病中的生物学，我们建议：1） 进一步表征脑和培养淋巴细胞中的 GDH 同工蛋白 患有各种退行性神经系统疾病和控制的患者。 2) 进一步表征对照和对照中的 GDH 特异性 mRNA 神经系统患者并确定他们是否代表不同的物种。 3) 从培养的淋巴细胞中分离和表征 GDH 特异性 cDNA 对 GDH 异常的神经系统患者进行研究以寻找该基因 导致酶活性改变的缺陷。 4) 表达突变体 异源细胞系统中的 cDNA 以表征酶 产生并探索这些突变对人类的因果关系 神经退行性疾病。此外，结构、组织和功能 人类 GDH 基因的数量将被确定。这些研究将奠定 为进一步分析上述疾病的基因组奠定了基础 DNA水平。