CHEMOTHERAPY AND MODELS OF HERITABLE SPHINGOLIPIDOSES

遗传性鞘脂血症的化疗和模型

• 批准号: 3310669
• 负责人: NORMAN S. RADIN
• 金额: $ 7.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-06-01 至 1987-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3310669
• 关键词: Gaucher's disease; Niemann Pick disease; brain metabolism; ceramides; chlorpromazine; chromatography; disease /disorder model; drug metabolism; glucosylceramidase; hydrolase; hydrolysis; lipid biosynthesis; mental retardation; metabolism disorder chemotherapy; metachromatic leukodystrophy; neural degeneration; radionuclides; radiotracer; sphingolipidosis; sphingolipids; sphingomyelins; sphingosine

Chemotherapy will be attempted for several genetic disorders of the sphingolipid hydrolases, in particular Gaucher disease and metachromatic leukodystrophy. The sphingolipidoses can be characterized by neurological degeneration, accumulation of sphingolipids in the tissues, mental retardation, degeneration of the long bones, severe pain, blindness, circulatory blockage due to organ swelling, and other symptoms. My plan is to block the accumulation of the affected sphingolipid by slowing its rate of synthesis, to match the activity of the defective - but functioning - hydrolase. The hydrolases will then be able to maintain turnover without net accumulation. I believe that many of the pathological symptoms will be alleviated as the stored lipids enter the normal metabolic pathways. This will be done by two approaches: (1) inhibition of the synthetic enzyme by administration of specific inhibitors or (2) stimulation of enzyme pathways that compete with the lipid-synthesizing enzyme for substrate. In the former case, compounds will be tested in normal mice using inhibitors that we have developed by in vitro assay of the enzyme which makes glucocerebroside. This should produce depressed levels of the sphingolipid and have potential use in Gaucher disease. In the latter case, slowing of cerebroside sulfate synthesis will be attempted by feeding normal mice (a) readily sulfated phenols, (b) a low-sulfur diet, (c) and/or known inhibitors of taurine transport. These approaches should deplete the body of sulfur-containing amino acids, which provide sulfate ions for the synthesis of the sulfosphingolipid. The approach may be helpful for patients with metachromatic leukodystrophy. Additional potential inhibitors will be synthesized for blocking the enzymes which form glucocerebroside, ceramide (for Farber's disease), and sphingomyelin (for Niemann-Pick disease). They will be tested first with in vitro assays, then with mice as above.

化疗将尝试用于几种遗传性疾病， 鞘脂水解酶，特别是戈谢病和异染性 脑白质营养不良 鞘脂病的特征可以是神经系统疾病。 组织中鞘脂的变性、蓄积、精神 发育迟缓，长骨退化，剧痛，失明， 由于器官肿胀导致的循环阻塞和其他症状。 我的计划是 通过减慢受影响的鞘脂的积累速率来阻断其积累 来匹配有缺陷但功能正常的 水解酶。 然后水解酶将能够保持周转， 净积累。 我相信很多病理症状 随着储存的脂质进入正常的代谢途径而减轻。 这 将通过两种方法进行：（1）通过以下方法抑制合成酶： 施用特异性抑制剂或（2）刺激酶途径 与脂质合成酶竞争底物。 在 在前一种情况下，将使用抑制剂在正常小鼠中测试化合物， 我们通过体外试验开发了一种酶， 葡糖脑苷脂 这应该会降低鞘脂的水平 并且在戈谢病中有潜在的用途。 在后一种情况下， 将通过喂养正常小鼠来尝试合成甘草酸苷硫酸盐（a） 容易硫酸化的酚，（B）低硫饮食，（c）和/或已知的 牛磺酸转运抑制剂。 这些方法应该消耗身体 含硫的氨基酸，它提供硫酸根离子， 磺基鞘脂的合成。 该方法可能有助于 异染性脑白质营养不良患者。 额外的潜在 将合成抑制剂来阻断形成 葡萄糖脑苷脂、神经酰胺（用于法伯病）和鞘磷脂（用于 尼曼-匹克病）。 它们将首先通过体外试验进行测试， 然后如上所述用小鼠。