GLUTAMIC DEHYDROGENASE IN NEUROLOGIC DISORDERS

我们实验室最近的研究表明， 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 迟发性神经元性脑病患者的神经组织 退行性疾病 本提案的长期目标 是双重的：第一是进一步表征不同的 GDH组分，并确定它们是否代表 基因决定的变体或翻译后产物 改性 第二个是定义精确的分子 导致酶活性改变的缺陷 在神经病患者身上发现的。 我们建议：1）进一步研究动力学和电泳 纯化的GDH形式的特征， 患者和对照的神经组织。 2)搜索 在酶的一级结构的差异在健康和 疾病 3)研究培养皮肤合成GDH的能力 成纤维细胞的患者和对照，并调查是否后 酶分子的翻译修饰发生在 人体组织，如果是这样的话，这是否是改变了在 疾病状态。 4)为了确定细胞的亚细胞定位， 大脑中的酶，以便更好地了解其在神经系统中的作用。 系统功能和功能障碍。 这些研究预计将 为克隆人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 紊乱

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.