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: 3397204
• 负责人: ANDREAS PLAITAKIS
• 金额: $ 26.11万
• 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/3397204
• 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 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)已被证明在 伴有系统萎缩的异质性神经疾病患者 其中谷氨酸代谢异常。有证据表明 可能由基因突变引起的不同的GDH异常可能 基础的临床和遗传异质性与减少 酶活性。因此，已经证明存在多种谷氨酸脱氢酶同功蛋白。 在人脑中，它们中的一些在N末端不同。这些都被发现了 在数量上不同地还原和在催化作用中改变 两种不同类型精神分裂症患者的脑内特性和功能 神经退行性疾病。此外，不同大小的多个mRNA 已被证明存在于各种哺乳动物组织中，包括人类 大脑以及多个谷氨酸脱氢酶基因。然而，目前仍不清楚是否 不同大小的mRNAs和Gdh同工蛋白由不同的 基因或由一个功能基因通过交替剪接和后剪接产生 翻译修饰过程。 回答这些问题并进一步阐明该酶在 神经系统生物学在健康和疾病中的作用，我们建议：1) 脑和培养淋巴细胞中GDH同工蛋白的进一步鉴定 患有各种退行性神经疾病的患者和对照组。 2)为了进一步鉴定对照组和对照组中GDH特异的mRNAs 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鉴定GdH特异性基因 神经科患者的GDH异常，以寻找基因 酶活性改变的原因是缺陷。4)表达突变体 异种细胞系统中的cDNA，以确定酶的特性 产生并探索这些突变对人类的因果关系 神经退行性变。此外，它的结构、组织和功能 人类谷氨酸脱氢酶基因的比例将被确定。这些研究将奠定 为进一步从基因组角度分析上述疾病奠定了基础 DNA水平。