CHEMOTHERAPY AND MODELS OF HERITABLE SPHINGOLIPIDOSES

将尝试对几种遗传性疾病进行化疗 鞘磷脂水解酶，特别是高谢病和异染性 脑白质营养不良。鞘脂沉积症可以表现为神经学特征。 神经鞘脂在组织中的退化和积聚 发育迟缓，长骨退化，剧烈疼痛，失明， 由于器官肿胀等症状导致的循环阻塞。我的计划是 通过减缓受影响的鞘脂的速度来阻止其积聚 合成，以匹配有缺陷但功能正常的人的活动 水解酶。水解酶将能够保持周转率，而不是 净积累。我相信很多病理症状都会 当储存的脂类进入正常的代谢途径时，情况会有所缓解。这 将通过两种方法完成：(1)通过以下方式抑制合成酶 给予特定的抑制剂或(2)刺激酶途径 它们与脂肪合成酶竞争底物。在 在前一种情况下，化合物将在正常小鼠身上使用抑制剂进行测试 我们已经开发了通过体外测试的酶，它使 葡萄糖脑苷。这应该会降低鞘磷脂的水平。 并有可能用于治疗高谢病。在后一种情况下，减慢 将尝试通过喂养正常小鼠来合成脑苷硫酸盐(A) (B)低硫饮食；(C)和/或已知 牛磺酸转运的抑制剂。这些方法应该会耗尽身体 含硫氨基酸，为硫酸盐提供离子 磺基鞘糖脂的合成。这种方法可能会对 异色性脑白质营养不良患者。额外的潜力 将合成抑制剂来阻断形成的酶 葡萄糖脑苷、神经酰胺(治疗Farber病)和鞘磷脂(治疗 尼曼-皮克病)。它们将首先通过体外测试进行测试， 然后用如上所述的老鼠。

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.