METABOLISM OF COMPLEX LIPIDS OF NERVOUS TISSUES

1.D型Niemann-Pick患者的代谢缺陷 疾病(新斯科舍省变种)已被证明是由于 异常的细胞内胆固醇稳态类似于， 但在某些方面与C型异常不同 尼曼-皮克病是本科以前发现的。这个 这些疾病中的分子损伤导致：(1)未能下调- 调节细胞膜上的低密度脂蛋白受体；(2)缺乏羽绒毛膜 胆固醇关键酶HMGCoA还原酶的调控 生物合成；以及(3)不能上调酰基胆固醇酰基 辅酶A转移酶，催化乙二醇酯化的酶 细胞内胆固醇。根据这些信息，我们有 开发的诊断C型和D型Niemann-Pick的测试 疾病和杂合子的鉴定。在87财年，这些 产前诊断的程序被证明是可靠的。 这些条件。 2.其他工作主要集中在合成和使用非 葡萄糖脑苷和葡萄糖脑苷的代谢类似物 半乳脑苷类药物对高雪氏病发病机制的研究 疾病和Krabbe病通过建立啮齿动物模型 各自的人类疾病。一种新的葡萄糖脑苷类似物 已经被合成，似乎对选择很有用 缺乏葡萄糖脑苷酶的突变细胞 缺乏高谢病。这些细胞将被用来 构建高雪病转基因小鼠模型。

1. The metabolic defect in patients with Type D Niemann-Pick disease (Nova Scotia variant) has been shown to be due to abnormal intracellular cholesterol homeostasis that resembles, but differs in some respects, from the abnormality in Type C Niemann-Pick disease previously discovered by this Branch. 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. Based on this information, we have developed tests for the diagnosis of Types C and D Niemann-Pick disease and the identification of heterozygotes. In FY 87 these procedures were shown to be reliable for the prenatal diagnosis of these conditions. 2. Other work has centered on the synthesis and use of non- metabolizable analogs of glucocerebroside and galactocerebroside to examine the pathogenesis of Gaucher's disease and Krabbe's disease by developing rodent models of the respective human disorders. A novel analog of glucocerebroside has been synthesized and 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.