METABOLISM OF COMPLEX LIPIDS OF NERVOUS TISSUES

神经组织复合脂质的代谢

• 批准号: 5203871
• 负责人: P G PENTCHEV
• 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/5203871
• 关键词: Alzheimer's disease; HMG coA reductases; Niemann Pick disease; acetyl coA acetyltransferase; artificial chromosomes; atherosclerosis; cellular pathology; cholesterol; esterification; gene mutation; gene therapy; homeostasis; human tissue; inborn metabolism disorder diagnosis; intracellular transport; lipid metabolism; lipid transport; low density lipoprotein; membrane transport proteins; molecular cloning; molecular pathology; nervous system; prenatal diagnosis; receptor expression; steroid biosynthesis

Types C and D Niemann-Pick disease are characterized by abnormal intracellular cholesterol homeostasis. The molecular lesion in these disorders causes: (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 have been developed and are now widely used in medical practice for the diagnosis of Types C and D Niemann-Pick disease, identification of heterozygotes, and the prenatal diagnosis of these conditions. We have linked the NP-C mutation to chromosome 18 by positional cloning. We have obtained partial correction of the defective cholesterol metabolism with YACs within the NP-C defined interval on chromosome 18 q11. Identification of the gene will enable us to assess direct DNA diagnosis and initiate protein and gene replacement studies. The Golgi apparatus has been shown to regulate lysosomal cholesterol transport. Characterization of the cholesterol transporter as identified by the NP- C mutation will provide the tools to begin to delineate the molecular mechanisms as well as cellular pathways of intracellular cholesterol transport. Armed with such information, we will study cholesterol processing in normal cells and in pathogenic conditions represented, not only by the NP-C cell, but also by other cholesterol lipidotic states such as atherosclerosis and potentially Alzheimer's disease.

C 型和 D 型尼曼-匹克病的特点是异常 细胞内胆固醇稳态。 这些分子损伤 疾病原因：（1）未能下调细胞上的 LDL 受体 膜； (2)缺乏关键酶HMGCoA还原酶的下调 胆固醇生物合成； (3) 无法上调酰基 胆固醇酰基 CoA 转移酶，催化 细胞内胆固醇的酯化。测试已经开发完成 现在广泛用于医疗实践中的类型诊断 C 和 D 尼曼匹克病、杂合子的鉴定以及 这些情况的产前诊断。 我们通过定位克隆将 NP-C 突变与 18 号染色体连接起来。 我们已经部分纠正了有缺陷的胆固醇 在 18 号染色体上 NP-C 定义的区间内与 YAC 进行代谢 q11。 基因的鉴定将使我们能够评估直接 DNA 诊断并启动蛋白质和基因替代研究。高尔基体 装置已被证明可以调节溶酶体胆固醇转运。 NP-鉴定的胆固醇转运蛋白的特征 C突变将提供工具来开始描绘分子 细胞内胆固醇的机制和细胞途径 运输。 有了这些信息，我们将研究胆固醇 代表正常细胞和致病条件下的加工，而不是 仅受 NP-C 细胞影响，还受其他胆固醇脂代谢状态影响 例如动脉粥样硬化和潜在的阿尔茨海默病。