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: 3397202
• 负责人: ANDREAS PLAITAKIS
• 金额: $ 14.84万
• 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 1990-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3397202
• 关键词: Parkinson's disease; aminoacid metabolism; blood chemistry; brain disorder diagnosis; brain mapping; cerebellar disorders; electrofocusing; enzyme mechanism; enzyme structure; fibroblasts; gene expression; genetic translation; glutamate dehydrogenase; human subject; isoleucine; laboratory rat; leucine; leukocytes; posttranslational modifications; protein biosynthesis; tissue /cell culture

Recent studies in our laboratory have shown that distinct forms of glutamate dehydrogenase are present in mammalian brain and that abnormalities of this enzyme occur in neural and extraneural tissues of patients with late onset neuro- degenerative disorders. The long-term objects of this proposal are twofold: The first is to further characterize the different GDH components and determine as to whether they represent genetically determined variants or products of post-translational modification. The second is to define the precise molecular defect(s) that are responsible for the altered enzyme activity found in the neurological patients. We propose: 1) to study further the kinetic and electrophoretic characteristics of the purified GDH forms from extraneural and neural tissues of patients and controls. 2) To search for differences in the primary structure of the enzyme in health and disease. 3) To study the synthesis of GDH by cultured skin fibroblasts of patients and controls and investigate whether post- translational modification(s) of the enzyme molecule occurs in human tissues, and if so as to whether this is altered in the disease state. 4) To determine the subcellular localization of the enzyme in brain in order to better understand its role in nervous system function and dysfunction. These studies are expected to lay the groundwork for cloning the human GDH gene(s) and exploring its possible polymorphism in human degeneratives disorders.

我们实验室最近的研究表明，不同的形式 哺乳动物大脑中存在谷氨酸脱氢酶 这种酶的异常发生在神经和 晚发性神经病患者的神经外组织 退行性疾病。 本提案的长期目标 有两个方面：第一个是进一步描述不同的特征 GDH 分量并确定它们是否代表 基因决定的变异体或翻译后产物 修改。 第二是定义精确的分子 导致酶活性改变的缺陷 发现于神经系统患者。 我们建议：1）进一步研究动力学和电泳 从神经外和纯化的 GDH 形式的特征 患者和对照的神经组织。 2) 搜索 健康和健康状态下酶的一级结构存在差异 疾病。 3) 研究培养皮肤合成GDH的情况 患者和对照的成纤维细胞，并研究后是否 酶分子的翻译修饰发生在 人体组织，以及是否会在 疾病状态。 4) 确定亚细胞定位 大脑中的酶，以便更好地了解其在神经中的作用 系统功能和功能失调。 这些研究预计将 为克隆人类 GDH 基因奠定基础 探索其在人类退行性疾病中可能的多态性 失调。