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: 3397203
• 负责人: ANDREAS PLAITAKIS
• 金额: $ 24万
• 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/3397203
• 关键词: Xenopus; aminoacid metabolism; brain; central nervous system disorders; degenerative motor system disease; egg /ovum; electrofocusing; electrophoresis; 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.

已证明谷氨酸脱氢酶（GDH）在体内显着减少 患有异质性神经系统疾病伴系统萎缩的患者， 谷氨酸代谢异常。有证据表明 可能由基因突变引起的明显GDH异常， 与减少的遗传相关的临床和遗传异质性的基础 酶活性因此，已显示存在多种GDH同工蛋白 在人脑中，其中一些在它们N-末端不同。这些是在 在数量上有差异地减少， 具有2种不同类型的脑血管病患者的脑中的性质和功能 神经退行性疾病此外，多种不同大小的mRNA 已显示存在于各种哺乳动物组织中，包括人类 脑以及多个GDH基因。然而，目前还不清楚是否 不同大小的mRNA和GDH同工蛋白由不相同的 基因或由一个功能基因通过选择性剪接和后 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的生物学，我们建议：1） 进一步表征脑和培养的淋巴细胞中的GDH同工蛋白 各种退行性神经系统疾病患者和对照组。 2)为了进一步表征对照组中的GDH特异性mRNA， 神经病患者，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并鉴定GDH特异性cDNA GDH异常的神经系统患者，以寻找基因 导致酶活性改变的缺陷。4)表达突变体 在异源细胞系统中的cDNA，以表征酶 并探索这些突变对人类的因果关系 神经退化此外，结构、组织和职能 将测定人GDH基因的总拷贝数。这些研究将奠定 在基因组水平上进一步分析上述疾病的基础工作 DNA水平。