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: 3397199
• 负责人: ANDREAS PLAITAKIS
• 金额: $ 13.78万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-12-01 至 1986-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3397199
• 关键词: aminoacid metabolism; autosomal recessive trait; blood chemistry; electrofocusing; electrophoresis; fibroblasts; gene expression; glutamate dehydrogenase; glutamates; human subject; human therapy evaluation; isoleucine; isozymes; leucine; leukocytes; nervous system disorder diagnosis; neural degeneration; tissue /cell culture

Recent studies in our laboratory revealed that a partial deficiency of glutamate dehydrogenase (GDH) and abnormal glutamate metabolism are specific biochemical defects of a form of recessively-inherited olivopontocerebellar atrophy (OPCA). Additional studies revealed evidence for the cellular presence of two distinct forms of GDH in human leukocytes and fibroblasts as well as in rat brain. One isoenzyme, which is "soluble", is heat resistant (at 47.5 C) where as the other isoenzyme, which is "particulate", is heat-labile (at 47.5 C). Determination of both GDH isoenzymes in leukocytes from patients with recessive OPCA revealed complete deficiency of the heatlabile GDH. These results strongly suggest that deficiency of the heat-sensitive GDH is the actual gene defect of this form of recessive OPCA. We propose: (1) To extend the current investigations on the activity of the two GDH isoenzymes in leukocytes from patients with OPCA as well as patients with other degenerative neurological disorders to further consolidate our data on the phenotype associated with GDH deficiency. (2) To investigate whether a deficiency of the heat-sensitive GDH is also present in cultured skin fibroblasts from these patients. (3) To evaluate the activities of the two GDH isoenzymes in leukocytes and cultured skin fibroblasts from obligated heterozygotes (parents and children of GDH-deficient patients). (4) To purify the rat and human brain and liver GDH isoenzymes and to compare their properties. (5) To further characterize the GDH isoenzymes in leukocytes and fibroblasts from patients and controls and to develop improved methods for their separation. (6) To expand the current studies on systemic metabolism of glutamate in patients with GDH deficiency as well as patients with other degenerative neurological disorders. (7) To further explore the possible role of GDH-activating agents such as the branched-chain amino acids in arresting or reversing the course of the GDH-deficient neurological disorders.

我们实验室最近的研究表明，部分缺乏 谷氨酸脱氢酶（GDH）和谷氨酸代谢异常是 隐性遗传的特定生化缺陷 橄榄脑桥小脑萎缩（OPCA）。 其他研究揭示了证据 人类白细胞中存在两种不同形式的 GDH 和成纤维细胞以及大鼠大脑中的细胞。 一种同工酶，它是 “可溶”，耐热（47.5°C），与其他同工酶一样， 它是“颗粒”，不耐热（47.5°C）。 两者的测定 隐性 OPCA 患者白细胞中的 GDH 同工酶被发现 不耐热的 GDH 完全缺乏。 这些结果强烈表明 热敏感 GDH 的缺乏是该基因的实际缺陷 隐性 OPCA 的形式。 我们建议： (1) 延长目前的 白细胞中两种 GDH 同工酶活性的研究 OPCA 患者以及其他退行性神经系统疾病患者 疾病进一步巩固我们与相关表型的数据 GDH 缺乏。 (2) 调查是否存在缺陷 热敏感 GDH 也存在于这些细胞培养的皮肤成纤维细胞中 患者。 (3) 评价两种GDH同工酶的活性 来自专性杂合子的白细胞和培养的皮肤成纤维细胞 （GDH 缺乏症患者的父母和孩子）。 (4)净化老鼠 和人脑和肝脏 GDH 同工酶并比较它们的特性。 (5) 进一步表征白细胞中的GDH同工酶和 来自患者和对照的成纤维细胞，并开​​发改进的方法 他们的分离。 (6) 拓展现有的全身代谢研究 GDH 缺乏症以及其他疾病患者的谷氨酸含量 退行性神经系统疾病。 （七）进一步探索可能的途径 GDH 激活剂（例如支链氨基酸）的作用 阻止或逆转 GDH 缺乏的神经系统疾病的进程 失调。