GLUTAMIC DEHYDROGENASE IN NEUROLOGIC DISORDERS

我们实验室最近的研究表明，不同的形式 谷氨酸脱氢酶存在于哺乳动物的大脑中， 这种酶的异常发生在神经和 迟发性神经性痴呆患者的神经外组织 退化性疾病。这项提议的长期目标 有两个方面：第一是进一步刻画不同的 Gdh组件并确定它们是否表示 翻译后基因决定的变体或产品 修改。第二个是定义精确的分子 导致酶活性改变的缺陷(S) 在神经科患者身上发现。 我们建议：1)进一步研究其动力学和电泳性 体外和体外纯化的谷氨酸脱氢酶形态的特性 患者和对照组的神经组织。2)搜索 健康人群和健康人群酶一级结构的差异 疾病。3)培养皮肤合成谷氨酸脱氢酶的研究 患者和对照组的成纤维细胞，并调查术后 酶分子的翻译修饰(S)发生在 人体组织，如果是这样的话，这是否会在 疾病状态。4)确定肿瘤细胞的亚细胞定位 大脑中的酶，以便更好地了解其在神经中的作用 系统功能和功能障碍。这些研究预计将 为克隆人谷氨酸脱氢酶基因奠定基础(S)和 探讨其在人类退行性疾病中的可能多态性 精神错乱。

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.