METABOLISM OF COMPLEX LIPIDS OF NERVOUS TISSUES

神经组织复合脂质的代谢

• 批准号: 3922451
• 负责人: R O BRADY
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3922451
• 关键词: Gaucher's disease; HMG coA reductases; Krabbe's disease; Niemann Pick disease; Rodentias; acyl coA; cerebrosides; cholesterol; disease /disorder model; esterification; gangliosides; genetically modified animals; human tissue; inborn metabolism disorder diagnosis; lipid metabolism; low density lipoprotein; model design /development; molecular pathology; prenatal diagnosis; sphingomyelins; tissue /cell culture

1. The metabolic defect in patients with Types C and D Niemann- Pick disease has been shown to be due to abnormal Intracellular cholesterol homeostasis. The molecular lesion in these disorders results in: (1) failure to down-regulate LDL receptors on cell membranes; (2) lack of down-regulation of HMGCoA reductase, a key enzyme in cholesterol biosynthesis; and (3) inability to up- regulate acyl cholesterol acyl CoA transferase, the enzyme that catalyzes the esterification of intracellular cholesterol. Tests for the diagnosis of Types C and D Niemann-Pick disease and the identification of heterozygotes, and the prenatal diagnosis of these conditions. 2. Other work has centered on the synthesis and use of non- metabolizable analogs of glucocerebroside to examine the pathogenesis of Gaucher's disease and to develop a rodent model of the human disorders. An analog of glucocerebroside has been synthesized that appears to be useful for the selection of mutagenized cells that lack glucocerebrosidase, the enzyme lacking in Gaucher's disease. These cells will be used to construct a transgenic murine analog of Gaucher's disease.

1. C型和D型尼曼氏病患者的代谢缺陷 皮克病已被证明是由于异常的细胞内 胆固醇稳态 这些疾病的分子损伤 结果：（1）未能下调细胞上的LDL受体 （2）缺乏HMGCoA还原酶的下调，这是一个关键的 胆固醇生物合成中的酶;和（3）不能上调- 调节酰基胆固醇酰基辅酶A转移酶，这种酶 催化细胞内胆固醇的酯化。 测试 用于诊断C型和D型尼曼-匹克病， 杂合子的鉴定和产前诊断 了以下条件 2. 其他工作集中在非物质的合成和使用上 葡萄糖脑苷脂的代谢类似物，以检查 高雪氏病的发病机制，并建立啮齿动物模型， 人类疾病 葡糖脑苷脂的类似物已经被 合成，似乎是有用的选择， 突变细胞缺乏葡萄糖脑苷脂酶，这种酶缺乏 高雪氏症的症状 这些细胞将用于构建 戈谢病的转基因小鼠类似物。